SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINES AS APELIN RECEPTOR AGONISTS

ABSTRACT

Provided herein are agonists of the apelin receptor of Formula (I):for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/637,652, filed Feb. 7, 2020, which is the U.S. National Stageapplication of International Application No. PCT/US2018/045837, filedAug. 8, 2018, and claims the benefit of priority to U.S. ProvisionalApplication No. 62/543,265, filed Aug. 9, 2017, all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates generally to small molecule agonists of theapelin receptor (APJ) and, more specifically, to small moleculecompounds for the treatment of apelin receptor-mediated diseases anddisorders.

BACKGROUND OF THE INVENTION

G protein-coupled receptors (GPCRs) are activated by a plethora ofmolecules including neuropeptides, polypeptide hormones and non-peptidessuch as biogenic amines, lipids, nucleotides and ions. They areclassically composed of seven membrane-spanning domains and constituteone of the largest and most diverse gene families in the mammaliangenome. Some novel GPCRs do not have obvious endogenous ligands and aretermed orphan receptors, a number of which appear to be constitutivelyactive. The cognate ligands for some of these orphan GPCRs have beenidentified, often based on the cellular and tissue distributions of theorphan GPCRs and occasionally using ‘reverse pharmacology’ where orphanGPCRs have been used to isolate novel endogenous substances. The humanapelin receptor (APJ, gene symbol APLNR) first identified in 1993 is onesuch GPCR whose endogenous ligand, apelin, has been described.

Both APJ and apelin have been implicated as the key mediators ofphysiological responses to multiple homeostatic perturbations, includingcardiovascular control, water balance, hypothalamic-pituitary-adrenal(HPA) axis regulation and metabolic homeostasis. Homeostatic stabilityis critical in mammalian organisms, and knowledge as to how this vitalfunction is regulated and how this mechanism can go wrong inpathological conditions is still limited.

APJ was first identified as an orphan GPCR, with closest identity to theangiotensin II (Ang II) receptor, type AT_(1a). APJ remained an orphanreceptor until 1998 when a 36-amino acid peptide termed apelin, for APJendogenous ligand was identified. In the ensuing years, the receptor wasdeorphanised when its cognate ligand, apelin, was isolated from bovinestomach extracts. Recently, the apelinergic system has been shown to becritically involved in multiple homeostatic processes.

The protein structure of APJ is typical of a GPCR, containing sevenhydrophobic transmembrane domains, with consensus sites forphosphorylation by protein kinase A (PKA), palmitoylation andglycosylation. The N-terminal glycosylation of GPCRs has been implicatedin receptor expression, stability, correct folding of the nascentprotein and ligand binding. Furthermore, the palmitoylation of theC-terminal tail has been reported to play a role in membrane associationand, combined with receptor phosphorylation, these fatty acidmodifications can influence the internalization, dimerization and ligandbinding of a GPCR. Structural studies on APJ have determined that aminoacids in both the N-terminal (e.g., Asp²³ and Glu²⁰) and C-terminalportions of the receptor are required for internalization.

The gene encoding human apelin, termed APLN, is located on chromosomeXq25-26.1 and possesses one intron within its open reading frame of ˜6kb. In rat and mouse, the genes are termed Apln and are located atchromosomal locations Xq35 and XA3.2 respectively. The core promoterregions of these genes have been identified as −207/−1 and −100/+74 bpin rats and humans respectively. Similar to APJ, a CAAT box, but no TATAbox, sequence is present in the rat and human promoter regions.Furthermore, rat and human preproapelin cDNAs do not have a classicalKozak consensus sequence surrounding the initiating methionine codon.

Human and bovine APLN cDNA sequences encode a 77-amino acidpreproprotein (preproapelin) containing a hydrophobic rich N-terminalregion, likely to be a secretory signal sequence. Bovine, human, rat andmouse preproapelin precursors have 76-95% homology and appear to existendogenously as a dimeric protein, as a consequence of disulfide bridgesformed between cysteine residues.

There are several mature forms of the apelin peptide. As the sequence ofthe purified peptide corresponded to the 36 C-terminal amino acids ofthe preproapelin protein, it was predicted that apelin-36 wouldconstitute a mature form of the peptide. Additionally, as the C-terminalportion of preproapelin also contained lysine (Lys, K) and arginine(Arg, R) residues, and given their potential as sites for proteolyticcleavage, the existence of apelin-17 and apelin-13 peptides waspredicted, along with a pyroglutaminated form of apelin-13((Pyr¹)apelin-13). These mature forms of apelin lack cysteine residuesand are probably only present in monomeric form. The likely secondarystructures of apelin-36 and apelin-13 have been determined in aqueoussolution, indicating that both possess an unordered structure. The aminoacid sequence homology of the mature apelin-36 peptide is more conservedbetween species than that of preproapelin, with 86-100% homology betweenbovine, human, rat and mouse amino acid sequences, while the 23C-terminal amino acids have 100% homology between species, suggesting animportant physiological role.

Although APJ does not bind Ang II, apelin-13 shares a limited homology(four amino acids) with the vasoconstrictive peptide. Moreover, AngI-converting enzyme 2 (ACE2), which catalyzes the C-terminal dipeptidecleavage of Ang I to Ang II, or Ang II to Ang 1-7, also acts onapelin-13 with a high catalytic efficiency, removing the C-terminalphenylalanine (Phe, F) residue. However, this cleavage may notinactivate the peptide, as the apelin isoform K16P, which lacks theterminal Phe, while ineffective at inducing receptor internalization orregulating blood pressure (BP) (effects associated with the fullpeptide), still binds to APJ and inhibits forskolin-stimulated cAMPproduction.

Although it is clear that APJ and apelin mRNAs and proteins are widelydistributed in the CNS and peripheral tissues, whether the levels ofmRNAs present in most of the regions of the brain and tissues arefunctionally relevant is not yet known.

Early studies of the expression of APJ mRNA by northern blot andquantitative PCR (qPCR) analyses have revealed strongest signals in thehuman caudate nucleus, corpus callosum, hippocampus, substantia nigra,subthalamic nucleus, medulla and spinal cord. Recently, the expressionof APJ mRNA has also been demonstrated in the human cortex andhippocampus using a sensitive GPCR gene array profilingmethod—interestingly, APJ transcripts have also been detected in humanbone marrow stromal cell lines. Transcriptomic analysis of multiplebrain regions of human donors has revealed a widespread centralexpression of APJ mRNA with high levels in samples including thehippocampus (e.g., CA4 region), habenular nuclei, paraventricularnucleus (PVN) of the thalamus, supraoptic nucleus (SON) of thehypothalamus and various hindbrain structures. The salient feature ofthese studies is that APJ has been reported to have a widespread centraldistribution; although the function of APJ in the majority of brainregions is unknown, foremost among those regions probably important froma functional perspective include the PVN and SON of the hypothalamus.

In the periphery, the expression of human APJ mRNA was originallyreported to be strongest in the spleen, with less expression beingreported for the small intestine, colonic mucosa and ovary. A broaderqPCR study has also reported strongest expression in the spleen, withhigh levels also being reported to be present in the placenta and weakerlevels in the lung, stomach and intestine. (Pyr¹)apelin-13-binding sitescan be found within the media and intimal layers of muscular arteriesand large elastic arteries and veins, while in the lung, apelin-bindingsites have a predominantly vascular localization. Furthermore, APJdistribution in cardiovascular tissues, as demonstrated byimmunohistochemistry (IHC), indicates APJ to be present in ventricularcardiomyocytes, vascular smooth muscle cells (VSMCs) and intramyocardialendothelial cells.

APJ binds numerous apelin isoforms and signals through various Gproteins to a variety of signaling pathways to culminate in differentpatterns of activation and desensitization that may be tissue- and celltype-specific. Recently, APJ has also been reported to heterodimerizewith other GPCRs and to signal in the absence of an endogenous ligand.

The C-terminal region of the apelin peptide may be responsible for itsoverall biological activity. N-terminal deletions of apelin-17 revealthat the 12 C-terminal amino acids may be the core requirements for theinternalization and biological potency of APJ. Apelin-17 induces theinternalization of APJ, which decreases with every N-terminal deletionto apelin-12, while the deletion of the terminal F amino acid results ina peptide that no longer internalizes APJ or affects arterial BP. TheN-terminal residues within the RPRL motif (residues 2-5) of apelin-13are critical for functional potency, and the C-terminal sequence KGPM(residues 8-11) is important for binding activity and forinternalization. In contrast, the five N-terminal and two C-terminalamino acids of apelin-17 are not required for binding of the peptide toAPJ or activation of receptor signaling (e.g., cAMP production).Although this may indicate a possible dissociation between theconformational states of the receptor responsible for receptor signalingand internalization, it is also possible that different ligand isoformsmay induce differential receptor trafficking and signaling. Thesestudies provide information on the structural importance of key apelinresidues critical for efficient binding, activity and internalization,which have proved significant in the design and synthesis of apelinanalogs.

Although progress has been made in recent years in clarifying thephysiological significance of apelin/APJ, much remains to be discoveredabout the expression of the apelinergic system and precisely how itaffects numerous physiological functions. Since the discovery of theapelin ligand, both apelin and APJ have been implicated as keyregulators of central and peripheral responses to multiple homeostaticperturbations. These include playing pivotal roles in the regulation ofcardiovascular function, angiogenesis, fluid homeostasis and energymetabolism and acting as neuroendocrine modulators of the HPA axisresponses to stress. It is becoming apparent that the apelinergic systemmay play a pathophysiological role within many of these regulatorysystems.

The central mRNA expression of preproapelin in regions of thehippocampus, hypothalamus, thalamus and midbrain shares a distributionpattern, as shown by ISHH, similar to that of angiotensinogen (Ang IIprecursor). Ang II is part of the rennin-angiotensin system (RAS), whichcontrols extracellular fluid volume and arterial vasoconstriction,thereby regulating mean arterial blood pressure (MABP). The centralactions of the RAS include the regulation of drinking behavior, saltappetite and VP secretion. Importantly, the RAS plays a critical role inthe pathogenesis of heart failure. Interestingly, apelin exerts manyphysiological effects that appear to oppose those exerted by Ang II.More recently, apelin has been shown to block many Ang II-initiatedprocesses, perhaps partly by dimerization between APJ and AT₁.

It is clear that apelin has both peripheral and central cardiovasculareffects. However, experiments carried out in animal models have yieldedconflicting results about the role of peripheral apelin in theregulation of vascular tone, with both pressor and depressor responsesbeing described. In anaesthetized intact rats, the overall effect ofperipherally administered apelin is the reduction of MABP. Thishypotensive action is blocked by the NOS inhibitor Nω-Nitro-L-argininemethyl ester, indicating a nitric oxide-mediated pathway. In consciousrats, the effect is even less clear, with both increases and decreasesin MABP being reported. Discrepancies among these reports may reflectthe conscious state of the animal or the different apelin isoforms usedin these studies; it is unknown which specific apelin peptide may beresponsible for the (patho)-physiological roles of apelin. Furtherevidence that APJ plays a role in the regulation of BP comes from astudy on mice with a global deletion of APJ, where a transient decreasein systolic BP observed in conscious wild-type (WT) mice following i.p.injection of (Pyr¹)apelin-13 is abolished in APJ KO mice. However, whileperipheral apelin is a vasodilator in the human saphenous vein, invessels denuded of endothelium, apelin acts as a vasoconstrictor.Therefore, peripheral apelin may act as an antihypertensive factor, andsensitivity to the peripheral administration of apelin might be alteredin hypertensive disease.

Additionally, the apelinergic system has an important role in cardiacfunction. In the isolated rat heart, infusion of apelin-16 induces apotent dose-dependent positive inotropic effect, with an EC, of 40-125pM in humans and ˜33 pM in rats, an effect also observed in the failingheart. In mice, administration of apelin increases myocardialcontraction while reducing cardiac preload and afterload, withoutcausing hypertrophy. Furthermore, apelin increases the shortening ofsarcomeres in cardiomyocytes, an effect that is impaired in isolatedventricular myocytes from apelin and APJ KO mice. Apelin KO mice have animpaired response to cardiac pressure overload, thus suggesting a rolefor apelin/APJ in the sustainability and amplification of the cardiacresponse to stress. There is also evidence for a role in essentialhypertension (EHT) as circulating levels of apelin-12 are decreased inpatients with EHT. Functionally, the apelinergic system plays a role inthe Cripto signaling pathway (which stimulates signaling by thetransforming growth factor Nodal or growth/differentiation factors 1 and3, via activin type IB and type IIB receptors) in mammalian cardiacmyogenesis.

Cardiovascular development defects have been reported in APJ KO mice,where a loss of homozygous mutants has been described, but not in apelinKO mice, indicating possible ligand-independent effects of the receptor.This effect may perhaps be explained by the recent report that APJsignals independently of apelin in response to cardiac mechanicalstretch. APJ KO embryos at E10.5, when lethality begins, have poorlydeveloped vasculature of the yolk sac, delayed formation of theatrioventricular cushion and unusually formed cardinal veins and dorsalaorta. APJ KOs that survive do not reveal any apparent morphologicaldifferences; however, they have decreased vascular smooth muscle layerrecruitment and myocardial defects including thinning of the myocardium,enlarged right ventricles and ventricular septal defects, suggesting aninvolvement of apelin/APJ signaling in cardiovascular development.

Apelin appears to have a role to play in the pathophysiology of thecardiovascular system—it has been implicated in vascular diseases, heartfailure, and ischemia and subsequent reperfusion. In vascular diseases,the expression of apelin is up-regulated in the atherosclerosis of humancoronary artery. Yet its role is undetermined, as conflicting evidencehas been found in KO studies, indicating both antagonistic and inducingroles for apelin in atherosclerotic formation. During heart failure,plasma apelin levels rise in the early stages of disease and stabilizeor lower as the condition develops. However, APJ mRNA is decreased inthe weakened and enlarged heart of humans with idiopathic dilatedcardiomyopath. Apelin may have a cardioprotective role in hypoxia andischemia, where the cardiac levels of apelin and APJ respectively areincreased. Apelin may also play a protective a role inischemia/reperfusion injury, although the method of signaling appears tobe independent of the characteristic myocardial kinase cascade, termedthe reperfusion injury salvage kinase pathway. Post-infarct treatmentwith (Pyr¹)apelin-13 reduces infarct size and increases HR, with along-term antioxidant cardioprotective action.

Apelin is an angiogenic factor and mitogen of endothelial cells.Significantly, apelin is required for the normal development of frogheart and formation of murine blood vessels. Additionally, thedevelopment of the retinal vasculature is stunted in apelin KO mice, andapelin is necessary for hypoxia-induced retinal angiogenesis, and isalso involved in non-neovascular remodeling of the retina.

The apelinergic system has been implicated in tumor neoangiogenesis. Inbrain tumors, the expression of apelin and APJ is up-regulated inmicrovascular proliferations, while tumor cell lines overexpressingapelin show increased growth. The pathophysiological effects of apelinin angiogenesis have also been reported for the liver, where theapelinergic system is a factor in portosystemic collaterization andsplanchnic neovascularization in portal hypotensive rats as well as inneovascularization during liver cirrhosis. However, apelin may havetherapeutic effects in ischemia recovery due to vessel regeneration andendothelial proliferation and blood vessel diameter regulation. Thesefindings indicate that apelin is a crucial factor for angiogenesis andthat there may be therapeutic potential in both the disruption of itssignaling (e.g., tumors) and the stimulation of APJ expression (e.g.,ischemia recovery).

The detection of APJ mRNA expression in areas of the brain critical forthe control of fluid homeostasis led to the hypothesis that apelin mayplay a role in the regulation of body fluid balance. VP, along with OT,is synthesized primarily in the neurons of the mPVN and SON, whichproject to the posterior pituitary and release the peptides into thesystemic circulation. The predominant endocrine function of VP from thissource is to increase water permeability in the renal collecting ductcells, thereby allowing the retention of water.

The regulatory actions of apelin on thirst and drinking behavior havebeen reported. In water-replete animals, a significant increase in waterintake is observed following i.p. or i.c.v. injection of apelin, whereasin other studies apelin has been reported to reduce water intake posti.c.v. injection or to have no effect. Additionally, in water-deprivedrats, an inhibitory effect or lack of any effect of apelin on drinkingbehavior is observed, while in apelin KO mice, the dehydration-induceddrinking response is comparable to that observed in WT mice. Theexpression of apelin and APJ mRNAs, and labelling ofapelin-immunoreactive magnocellular cells, are increased by dehydration,while the labelling of VP-immunoreactive cells decreases, implying thedifferential regulation of these peptides in response to dehydration.Recently, however, abnormal fluid homeostasis has been demonstrated inAPJ KO mice, manifested by a decrease in drinking behavior and aninability to concentrate urine to levels observed in controls duringwater deprivation, suggesting an antidiuretic effect of apelin in vivo.However, in lactating rats, apelin induces diuresis and has directeffects on renal vasculature. APJ is also necessary indehydration-induced signaling in the subfornical organ, implicating theapelinergic pathway in responses to hyperosmotic stimuli.

A number of studies have pointed out an emerging involvement of apelinin energy metabolism and a role for adipocyte-derived apelin in the(patho)-physiology of obesity has been reported. Both apelin and APJmRNAs are present in mouse, human and rat adipose tissue, and theirlevels increase in adipose tissue and plasma with obesity. Thishighlights APJ as an intriguing therapeutic target for metabolicdisorders. However, the expression of plasma apelin is increased only inobese humans and in mouse models of obesity associated withhyperinsulinemia, indicating that obesity or high-fat feeding may not bethe main cause for the rise in the expression of apelin, and implying aclose relationship between apelin and insulin both in vivo and in vitro.Insulin directly acts on adipocytes in vitro to stimulate the productionof apelin, and the expression of apelin mRNA is down-regulated in theadipocytes of mice treated with the β-cell toxin streptozotocin, whichleads to a fall in plasma insulin levels. In mice, nutritional statusinfluences apelin levels in vivo—fasting inhibits plasma levels, whichare then restored by re-feeding—thus strengthening the implication thatinsulin regulates apelin gene expression and secretion. Additionally,apelin, perhaps through APJ expressed in pancreatic islet β-cells,regulates the secretion of insulin—apelin inhibits glucose-stimulatedinsulin secretion in vivo in mice and in isolated islets of Langerhansin vitro. Interestingly, in a recent study, apelin has been shown toalleviate diabetes-induced reduction of pancreatic islet mass and toimprove the insulin content of pancreatic islets in type 1 diabeticmice.

Apelin may have a positive effect in the metabolic syndrome (acombination of risk factors that when occurring together increase therisk of coronary artery disease, stroke and type 2 diabetes (T2D)).Apelin KO mice have reduced insulin sensitivity, are glucose intolerantand are hyperinsulinemic. The peripheral administration of apelinreduces peak plasma glucose concentrations by increasing glucose uptakein skeletal muscle and adipose tissue and improves insulin sensitivityin both apelin KO and obese high-fat diet fed mice, with theinsulin-sensitizing effects continuing for up to 4 weeks, with notolerance to the actions of apelin. Apelin increases glucose uptake,both in vitro and in vivo, through both insulin-dependent and-independent pathways. Apelin may also decrease body adiposity,independently of altered food intake, by increasing energy expenditurethrough the activation of mitochondrial uncoupling proteins 1 and 3.Clinical studies have shown a promising therapeutic value for apelin, asapelin displays beneficial glucose-lowering effects in human adiposetissue and plasma apelin levels correlate with glucose and HbA1c levels.Apelin is linked to the pathogenesis of T2D—plasma apelin concentrationsare increased in insulin-resistant patients, in type T2D patients and inmorbidly obese T2D individuals, perhaps indicating a compensatory roleof apelin in the reduction of insulin resistance. However, conversely,plasma apelin levels are reduced in newly diagnosed T2D patients andincreased in T2D patients and obese non-diabetic individuals. Theincreased expression of apelin in plasma and adipose tissue of obeseindividuals can, however, be reversed by a hypocaloric diet. A s aresult of such studies, similarities between the function of apelin andthat of insulin, and a link between this adipokine and glucosehomeostasis, have been hypothesized.

As has been noted previously, APJ is localized in the hypothalamic pPVNand the anterior pituitary gland, key areas involved in the stressresponse. Apelin mRNA is also present in these areas, co-localizing withVP in the mPVN, SON and pituitary. Additionally, apelin immunostainingof cell bodies and fibers is highest in the hypothalamus, with largenumbers of apelin-positive cell bodies present in the PVN and SON. Thepresence of APJ and apelin in VP- and CRH-containing hypothalamicnuclei, which are pivotal to the HPA axis responses to stress, suggestsa role for apelin/APJ in neuroadenohypophysial hormone release.

A role for apelin in the regulation of the HPA axis responses to stressis supported by studies showing that central administration of(Pyr¹)apelin-13 increases the expression of c-fos, an indicator ofneuronal activity, in the PVN. Furthermore, administration of apelin-13stimulates the release of CRH and VP from hypothalamic extracts invitro, effects consistent with stimulation of the stress axis. APJ mRNAlevels increase in the PVN in response to acute and chronic stress andfollowing adrenalectomy, implying negative regulation of the expressionof APJ mRNA by glucocorticoids. Additionally, dexamethasone, aglucocorticoid agonist, decreases apelin mRNA levels in 3T3-L1 mouseadipocytes.

Apelin may potentially stimulate the secretion of ACTH either directlyat the level of the pituitary corticotroph or via an indirect action onthe hypothalamus involving the release of both VP and CRH. Consistentwith the expression of apelin and APJ in anterior pituitarycorticotrophs, administration of apelin-17 directly increases therelease of ACTH, while also augmenting K+-stimulated ACTH release, in anex vivo perfusion system of anterior pituitary glands, suggestingpossible autocrine or paracrine functions for apelin in this tissue.Central administration of (Pyr¹)apelin-13 in rats also increases plasmaACTH and CORT levels while decreasing prolactin, luteinizing hormone andfollicle-stimulating hormone levels. However, increases in plasma ACTHand CORT levels observed after i.c.v. administration of (Pyr¹)apelin-13in mice are reduced to control levels by pre-treatment with the CRHreceptor antagonist α-helical CRH₉₋₄₁, while (Pyr¹)apelin-13-mediatedincreases in plasma ACTH levels are abolished in VP V1b receptor KOmice, indicating that apelin also modulates the release of ACTH via anindirect action on the hypothalamus involving both CRH- and VP-dependentmechanisms. Recently, using APJ KO mice, APJ has been shown to play aregulatory role in the modulation of the HPA axis responses to someacute stressors including LPS challenge (an immune stressor),insulin-induced hypoglycemia (a metabolic stressor) and forced swim (aphysical/psychological stressor). These studies suggest that otherpeptides cannot compensate for the loss of APJ to directly, orindirectly, induce the release of ACTH in response to stress. Thus, theintegration of neurobehavioral responses to stress may be morecomplicated than previously envisioned, with apelin/APJ exerting apivotal neuroregulatory role.

Apelin was first isolated from stomach extracts, and studies on theactions of apelin in the gastrointestinal system have found functional,and possible cell survival, roles. In the gastrointestinal system,apelin/APJ may be regulators of hormone and gastric acid secretion.Apelin/APJ may also have a direct effect on vascular smooth muscle,including vasoconstriction, which may affect renal glomerularhemodynamic function in the rat kidney. Some studies have also proposedan immunological role for apelin as it reduces the production ofcytokines in mouse spleen cells, suggesting that apelin may modulateneonatal immune responses through rodent and bovine colostrum and milk.APJ is also a co-receptor of HIV entry into target cells, an action thatis blocked by apelin. APJ may contribute to HIV-1 infection andpathogenesis in CNS-based cells as viral envelope proteins can mediatefusion with APJ-positive, cluster of differentiation 4 (CD4)-negativecells, provided that CD4 is added in trans, and HIV can infectAPJ-expressing cells despite their CD4 status. Other possible roles forapelin and APJ in the rodent CNS include antinociception, enhancement ofdepressive behavior, and facilitation of passive avoidance learning.Apelin may also have a role in neuroprotection, as apelin pre-treatmentprotects hippocampal neurones against N-methyl-D-aspartate (NMDA)receptor-mediated excitotoxic injury, possibly via the phosphorylationof Akt and ERK1/2, and prevents apoptosis in cultured mouse corticalneurones.

Furthermore, apelin and APJ are expressed in osteoblasts where they mayinduce cell proliferation and promote survival; however, an increase inbone mass can be observed in apelin KO mice. Recently, apelin has beenreported to have a potential role in the pathophysiology ofosteoarthritis (OA), as apelin is present in synovial fluid, and OApatients have elevated plasma apelin concentrations. Blood plasma levelsof apelin are reduced in patients with polycystic ovary syndrome,consistent with the role played by apelin/APJ in metabolic disturbancessuch as insulin resistance.

Elevated levels of apelin have been detected in many pathological statesor disease processes, such as heart disease, atherosclerosis, tumorangiogenesis and diabetes. However, in many systems, apelin has beenshown to have positive effects, for example in the cardiovascularsystem, where it has a cardioprotective effect. This has led tospeculation that apelin and APJ could be beneficial targets fortherapeutic strategies for a number of diseases and disorders.

To date, there are few reports of selective small molecule apelinreceptor agonists, and thus far none of the reported agonists havefavorable pharmacokinetic profiles. There is a need, therefore, forpotent compounds that target and exhibit dose dependent agonism of theapelin receptor.

SUMMARY OF THE INVENTION

The present invention is based on the seminal discovery of a series ofpotent small molecule pyrazolopyrimidine based agonists of the apelinreceptor, which are useful for the treatment of diseases including heartfailure, chronic kidney disease, hypertension, and metabolic disorderssuch as insulin resistance/diabetes and obesity. The compounds disclosedherein are highly specific for the apelin receptor versus theangiotensin II receptor (AT1).

Provided herein are compounds of structural Formula I, or apharmaceutically acceptable salt, polymorph, solvate, tautomer, orN-oxide thereof:

wherein:

R¹ and R² are each independently selected from the group consisting ofH, halogen, cyano, optionally substituted alkyl, aryl, alkoxy, phenoxy,amino, aniline, —CO₂H, —CO₂R⁶, or —CON(R⁷)₂;

R³ is selected from the group consisting of hydrogen, —CN, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl,haloalkoxy, optionally substituted phenyl, and optionally substituted 5-or 6-membered heteroaryl;

R⁴ is selected from the group consisting of hydrogen, —CN, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl,haloalkoxy, optionally substituted phenyl, and optionally substituted 5-or 6-membered heteroaryl;

R⁵ is selected from the group consisting —CO₂H, —CO₂R⁸, or —CON(R⁹)₂,optionally substituted alkyl, aryl, and alkoxy; and

R⁶-R⁹ are each independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted alkoxy, haloalkyl, haloalkoxy, optionally substitutedphenyl, optionally substituted amino, and optionally substituted 5- or6-membered heteroaryl. 1. In other aspects, the compounds providedherein are methyl7-(tert-butyl)-2-methyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,7-(tert-butyl)-2-methyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2,7-dimethyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2-methyl-7-(methylethyl)-3-(4-methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,7-cyclopropyl-2-methyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(4-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(4-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(4-methoxyphenyl)-2-methyl-5-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-7-carboxylicacid, ethyl2-cyclopropyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2-cyclopropyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2-ethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxamide,N-methyl[2-methyl-7-(methylethyl)-3-phenyl(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]carboxamide,N,N-dimethyl[2-methyl-7-(methylethyl)-3-phenyl(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]carboxamide,2-{[2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidin-5-yl]carbonylamino}aceticacid, ethyl3-(3-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2-methyl-7-(methylethyl)-3-(2-methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(3-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(3-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(3-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl2-methyl-7-(methylethyl)-3-(3-methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2-methyl-7-(methylethyl)-3-(3-methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(3-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(3-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl7-ethyl-2-methyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,7-ethyl-2-methyl-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl2-methyl-3-phenyl-7-propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2-methyl-3-phenyl-7-propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl2,6-dimethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2,6-dimethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2,6-dimethoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,4-(methylethyl)-5,7,8,9,10-pentahydro-5H-pyrimidino[1,2-b]indazole-2-carboxylicacid, ethyl3-(2,4-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,4-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(4-methoxy-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(4-fluoro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(4-methoxy-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(6-fluoro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(4-fluoro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(6-fluoro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-methyl-7-propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2,7-dimethyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2,7-dimethyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-7-ethyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2,6-dimethylphenyl)-7-cyclopropyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2,6-dimethylphenyl)-7-cyclobutyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-cyclobutyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidin-5-yl]methan-1-ol,1-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan-1-ol,1-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan-1-one,ethyl3-(6-methoxy-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(4-chloro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-[2-(ethoxycarbonyl)-6-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-cyclopentyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-7-cyclopentyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(4-chloro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-cyclopropyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-ethyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl2,7-bis(methylethyl)-3-(2,6-dimethylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-ethyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carbohydroxamicacid,3-(2-methoxy-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-[6-(ethoxycarbonyl)-2-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-7-(methylethyl)-2-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-(methylethyl)-2-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2,7-bis(methylethyl)-3-(2,6-dimethylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-cyclobutyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-methyl-7-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-cyclopropyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2-carboxy-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-(hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-(hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-2-(methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-(methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,2-[(dimethylamino)methyl]-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(6-fluoro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(6-fluoro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(6-chloro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(6-chloro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-2-(methoxycarbonyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-methyl-7-morpholin-4-yl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-morpholin-4-yl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-methoxy-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl2-(N,N-dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,2-(N,N-dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-(methylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,7-(dimethylamino)-3-(2,6-dimethylphenyl)-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-difluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-difluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-(4-methylpiperazinyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-phenoxy-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dimethylphenyl)-2-methyl-7-(4-methylpiperazinyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2,6-dimethylphenyl)-2-methyl-7-phenoxy-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-ylamine,N-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidin-5-yl]acetamide,ethyl3-(2-chloro-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2-chloro-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-dichlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dichlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2,6-diethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,ethyl3-(2,6-dimethylphenyl)-2-methyl-7-(phenylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-(phenylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(6-chloro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2-cyano-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(6-ethyl-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-2-methyl-7-pyrrolidinyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-pyrrolidinyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-2-methyl-7-piperidyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-piperidyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-(4-pyridyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-cyclopent-1-enyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-[6-(hydroxymethyl)-2-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, ethyl3-(2-bromo-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2-bromo-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-[6-(methoxymethyl)-2-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-7-[(4-chlorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-2-methyl-7-[(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-7-[(4-methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethyl)phenyl]amino}-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-7-[(4-cyanophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-[(4-chlorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-[(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-[(4-methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethyl)phenyl]amino}-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-[(4-cyanophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-2-methyl-7-(methylphenylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,methyl3-(2,6-dimethylphenyl)-2-methyl-7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-piperazinyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-2-methyl-7-(methylpropylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-cyclohex-1-enyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-cyclohexyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid,3-(2,6-dimethylphenyl)-7-(2-furyl)-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid, methyl3-(2,6-dimethylphenyl)-2-methyl-7-(methylpropylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate,3-(2,6-dimethylphenyl)-2-methyl-7-(4-1,2,5,6-tetrahydropyridyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylicacid and methyl3-(2,6-dimethylphenyl)-7-chloro-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate.

Provided herein are compounds having a structural formula as disclosedin Table 1.

TABLE 1 Compound Potency Number Structure Name Category 1

methyl 7-(tert-butyl)-2-methyl-3- phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 2

7-(tert-butyl)-2-methyl-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 3

2-methyl-7-(methylethyl)-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 4

2,7-dimethyl-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5- carboxylicacid A 5

2-methyl-7-(methylethyl)-3-(4- methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 6

7-cyclopropyl-2-methyl-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 7

7-(methylethyl)-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5- carboxylicacid A 8

3-(4-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 9

3-(4-methoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 10

3-(4-methoxyphenyl)-2-methyl-5- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-7-carboxylic acid A 11

ethyl 2-cyclopropyl-7-(methylethyl)-3- phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 12

2-cyclopropyl-7-(methylethyl)-3- phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 13

2-ethyl-7-(methylethyl)-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 14

2-methyl-7-(methylethyl)-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxamide A 15

N-methyl[2-methyl-7-(methylethyl)-3- phenyl(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]carboxamide A 16

N,N-dimethyl[2-methyl-7- (methylethyl)-3-phenyl(8-hydropyrazolo[1,5-a]pyrimidin-5- yl)]carboxamide A 17

2-{[2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidin-5- yl]carbonylamino}acetic acid A 18

ethyl 3-(3-methoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 19

ethyl 3-(2-chlorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 20

2-methyl-7-(methylethyl)-3-(2- methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid C 21

3-(2-chlorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 22

3-(3-methoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 23

ethyl 3-(2-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 24

3-(2-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 25

ethyl 3-(3-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 26

3-(3-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 27

ethyl 2-methyl-7-(methylethyl)-3-(3- methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 28

2-methyl-7-(methylethyl)-3-(3- methylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 29

ethyl 3-(2-methoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 30

ethyl 3-(3-chlorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 31

3-(2-methoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 32

3-(3-chlorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 33

ethyl 7-ethyl-2-methyl-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 34

7-ethyl-2-methyl-3-phenyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 35

ethyl 2-methyl-3-phenyl-7-propyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 36

2-methyl-3-phenyl-7-propyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 37

methyl 2,6-dimethyl-7-(methylethyl)-3- phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 38

2,6-dimethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 39

ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 40

ethyl 3-(2,6-dimethoxyphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 41

3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid D 42

3-(2,6-dimethoxyphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 43

4-(methylethyl)-5,7,8,9,10-pentahydro- 5H-pyrimidino[1,2-b]indazole-2-carboxylic acid A 44

ethyl 3-(2,4-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 45

3-(2,4-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 46

ethyl 3-(4-methoxy-2,6- dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 47

ethyl 3-(4-fluoro-2,6-dimethylphenyl)- 2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 48

3-(4-methoxy-2,6-dimethylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 49

ethyl 3-(6-fluoro-2-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 50

3-(4-fluoro-2,6-dimethylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid C 51

3-(6-fluoro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid B 52

ethyl 3-(2,6-dimethylphenyl)-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 53

3-(2,6-dimethylphenyl)-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 54

ethyl 3-(2,6-dimethylphenyl)-2-methyl- 7-propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 55

3-(2,6-dimethylphenyl)-2-methyl-7- propyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 56

ethyl 3-(2,6-dimethylphenyl)-2,7- dimethyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 57

3-(2,6-dimethylphenyl)-2,7-dimethyl-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 58

ethyl 3-(2,6-dimethylphenyl)-7-ethyl-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 59

ethyl 3-(2,6-dimethylphenyl)-7- cyclopropyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 60

ethyl 3-(2,6-dimethylphenyl)-7- cyclobutyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 61

3-(2,6-dimethylphenyl)-7-cyclobutyl-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid C 62

[3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidin-5-yl]methan-1-ol A 63

1-[3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan- 1-ol A 64

1-[3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)(8-hydropyrazolo[1,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan- 1-one A 65

ethyl 3-(6-methoxy-2-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 66

ethyl 3-(4-chloro-2,6-dimethylphenyl)- 2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 67

ethyl 3-[2-(ethoxycarbonyl)-6- methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 68

3-(2,6-dimethylphenyl)-7-cyclopentyl- 2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid B 69

ethyl 3-(2,6-dimethylphenyl)-7- cyclopentyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 70

3-(4-chloro-2,6-dimethylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 71

3-(2,6-dimethylphenyl)-7-cyclopropyl- 2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid B 72

3-(2,6-dimethylphenyl)-7-ethyl-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 73

ethyl 2,7-bis(methylethyl)-3-(2,6- dimethylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 74

3-(2,6-dimethylphenyl)-2-ethyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 75

3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carbohydroxamic acid C 76

3-(2-methoxy-6-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 77

3-[6-(ethoxycarbonyl)-2-methylphenyl]- 2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid C 78

ethyl 3-(2,6-dimethylphenyl)-7- (methylethyl)-2-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 79

3-(2,6-dimethylphenyl)-7- (methylethyl)-2-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 80

2,7-bis(methylethyl)-3-(2,6- dimethylphenyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 81

3-(2,6-dimethylphenyl)-2-cyclobutyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid A 82

ethyl 3-(2,6-dimethylphenyl)-2-methyl- 7-phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 83

3-(2,6-dimethylphenyl)-2-methyl-7- phenyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 84

3-(2,6-dimethylphenyl)-2-cyclopropyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid A 85

3-(2-carboxy-6-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 86

ethyl 3-(2,6-dimethylphenyl)-2- (hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 87

3-(2,6-dimethylphenyl)-2- (hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 88

methyl 3-(2,6-dimethylphenyl)-2- (methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 89

3-(2,6-dimethylphenyl)-2- (methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 90

2-[(dimethylamino)methyl]-3-(2,6- dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 91

ethyl 3-(6-fluoro-2-methoxyphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 92

3-(6-fluoro-2-methoxyphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 93

3-(6-chloro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid B 94

ethyl 3-(6-chloro-2-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 95

methyl 3-(2,6-dimethylphenyl)-2- (methoxycarbonyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 96

3-(2,6-dimethylphenyl)-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-2,5-dicarboxylic acid A 97

ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-morpholin-4-yl-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 98

3-(2,6-dimethylphenyl)-2-methyl-7- morpholin-4-yl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 99

3-(2,6-dimethylphenyl)-7-methoxy-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 100

ethyl 2-(N,N-dimethylcarbamoyl)-3- (2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 101

2-(N,N-dimethylcarbamoyl)-3-(2,6- dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 102

3-(2,6-dimethylphenyl)-2-methyl-7- (methylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 103

7-(dimethylamino)-3-(2,6- dimethylphenyl)-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 104

3-(2,6-difluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 105

ethyl 3-(2,6-difluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 106

3-(2,6-dimethylphenyl)-2-methyl-7-(4- methylpiperazinyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 107

3-(2,6-dimethylphenyl)-2-methyl-7- phenoxy-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 108

ethyl 3-(2,6-dimethylphenyl)-2-methyl- 7-(4-methylpiperazinyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 109

ethyl 3-(2,6-dimethylphenyl)-2-methyl- 7-phenoxy-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 110

3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-ylamine A 111

N-[3-(2,6-dimethylphenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidin-5-yl] acetamide A 112

ethyl 3-(2-chloro-6-fluorophenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 113

3-(2-chloro-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid A114

ethyl 3-(2,6-dichlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 115

3-(2,6-dichlorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 116

ethyl 3-(2,6-diethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate B 117

ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-(phenylamino)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylate A 118

3-(2,6-dimethylphenyl)-2-methyl-7- (phenylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 119

3-(6-chloro-2-methoxyphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 120

3-(2-cyano-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid A 121

3-(6-ethyl-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid A 122

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-pyrrolidinyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 123

3-(2,6-dimethylphenyl)-2-methyl-7- pyrrolidinyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 124

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-piperidyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 125

3-(2,6-dimethylphenyl)-2-methyl-7- piperidyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 126

3-(2,6-dimethylphenyl)-2-methyl-7-(4- pyridyl)-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 127

3-(2,6-dimethylphenyl)-7-cyclopent-1- enyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 128

3-[6-(hydroxymethyl)-2-methylphenyl]- 2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid D 129

ethyl 3-(2-bromo-6-methylphenyl)-2- methyl-7-(methylethyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 130

3-(2-bromo-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid B131

3-[6-(methoxymethyl)-2- methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[1,5- a]pyrimidine-5-carboxylic acid D 132

methyl 3-(2,6-dimethylphenyl)-7-[(4- fluorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 133

methyl 3-(2,6-dimethylphenyl)-7-[(4- chlorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 134

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-[(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 135

methyl 3-(2,6-dimethylphenyl)-7-[(4- methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 136

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-{[4-(trifluoromethyl)phenyl]amino}-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 137

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A 138

methyl 3-(2,6-dimethylphenyl)-7-[(4- cyanophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 139

3-(2,6-dimethylphenyl)-7-[(4- fluorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 140

3-(2,6-dimethylphenyl)-7-[(4- chlorophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 141

3-(2,6-dimethylphenyl)-2-methyl-7-[(4- methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 142

3-(2,6-dimethylphenyl)-7-[(4- methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 143

3-(2,6-dimethylphenyl)-2-methyl-7-{[4- (trifluoromethyl)phenyl]amino}-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 144

3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8- hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 145

3-(2,6-dimethylphenyl)-7-[(4- cyanophenyl)amino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 146

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-(methylphenylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 147

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-[methyl(4-methylphenyl)amino]-8- hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A148

3-(2,6-dimethylphenyl)-7-[(4- fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 149

3-(2,6-dimethylphenyl)-2-methyl-7- [methyl(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 150

3-(2,6-dimethylphenyl)-2-methyl-7- [methyl(4-methylphenyl)amino]-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 151

3-(2,6-dimethylphenyl)-7-[(4- fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 152

3-(2,6-dimethylphenyl)-2-methyl-7- piperazinyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 153

3-(2,6-dimethylphenyl)-2-methyl-7- (methylpropylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 154

3-(2,6-dimethylphenyl)-7-cyclohex-1- enyl-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 155

3-(2,6-dimethylphenyl)-7-cyclohexyl-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 156

3-(2,6-dimethylphenyl)-7-(2-furyl)-2- methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylic acid A 157

methyl 3-(2,6-dimethylphenyl)-2- methyl-7-(methylpropylamino)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylate A 158

3-(2,6-dimethylphenyl)-2-methyl-7-(4- 1,2,5,6-tetrahydropyridyl)-8-hydropyrazolo[1,5-a]pyrimidine-5- carboxylic acid A 159

methyl 3-(2,6-dimethylphenyl)-7- chloro-2-methyl-8-hydropyrazolo[1,5-a]pyrimidine-5-carboxylate A

Also provided herein is a pharmaceutical composition comprising acompound listed above or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable excipient.

A method of preventing or treating in a subject an apelin-mediateddisease or disorder, comprising administering to the subject apharmaceutical a compound listed above, thereby preventing or treatingthe disease or disorder is also provided herein. In one embodiment, thesubject is a human.

In certain aspects the disease or disorder is a cardiovascular diseaseor disorder, coronary heart disease, stroke, heart failure, systolicheart failure, diastolic heart failure, diabetic heart failure, heartfailure with preserved ejection fraction, cardiomyopathy, myocardialinfarction, left ventricular dysfunction, left ventricular dysfunctionafter myocardial infarction, cardiac hypertrophy, myocardial remodeling,myocardial remodeling after infarction, myocardial remodeling aftercardiac surgery or valvular heart disease.

In other aspects the disease or disorder is a metabolic disease ordisorder, metabolic syndrome, insulin resistance, diabetes mellitus,diabetic late complications, diabetic macro- and micro-vasculopathies,diabetic nephropathy, diabetic retinopathy, diabetic neuropathies orcardiac autonomic neuropathy.

In further aspects the disease or disorder is caused by CNS-dependent orCNS-independent disturbed fluid homeostasis, acute or chronic renalfailure, hypertension, pulmonary hypertension, portal hypertension orsystolic hypertension.

In other aspects, the disease or disorder is a vascular disease ordisorder, vascular permeability, nonfunctional blood vessels, vascularhypertrophy, vascular remodeling, vascular stiffness, atherosclerosis,peripheral arterial occlusive disease (PAOD), restenosis, thrombosis,vascular permeability disorders, ischemia, reperfusion damage, ischemiaor reperfusion damage of the heart, kidney or retina, or a combinationthereof.

In still other aspects, the disease or disorder is an infectiousdisease.

Other aspects and advantages of the invention will be apparent from thefollowing description and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 . NOE experiments proving the structural assignment ofregioisomers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the seminal discovery of a series ofpotent small molecule pyrazolopyrimidine based agonists of the apelinreceptor, which are useful for the treatment of diseases including heartfailure, chronic kidney disease, hypertension, and metabolic disorderssuch as insulin resistance/diabetes and obesity. The compounds disclosedherein are highly specific for the apelin receptor versus theangiotensin II receptor (AT1).

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to particularcompositions, methods, and experimental conditions described, as suchcompositions, methods, and conditions may vary. It is also to beunderstood that the terminology used herein is for purposes ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyin the appended claims.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural references unless the contextclearly dictates otherwise. Thus, for example, references to “themethod” includes one or more methods, and/or steps of the type describedherein which will become apparent to those persons skilled in the artupon reading this disclosure and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” is used, where n₁ and n₂ are the numbers, then unless otherwisespecified, this notation is intended to include the numbers themselvesand the range between them. This range may be integral or continuousbetween and including the end values. By way of example, the range “from2 to 6 carbons” is intended to include two, three, four, five, and sixcarbons, since carbons come in integer units. Compare, by way ofexample, the range “from 1 to 3 μM (micromolar)” which is intended toinclude 1 μM, 3 μM, and everything in between to any number ofsignificant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

The term “about” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, or any other moiety were the atom attached to thecarbonyl is carbon. An “acetyl” group, which is a type of acyl, refersto a —C(O)CH₃ group. An “alkylcarbonyl” or “alkanoyl” group refers to analkyl group attached to the parent molecular moiety through a carbonylgroup. Examples of such groups include methylcarbonyl and ethylcarbonyl.Examples of acyl groups include formyl, alkanoyl and aroyl.

The term “alkenyl” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—),(—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like.

The term “alkylene” as used herein, alone or in combination, refers to asaturated aliphatic group derived from a straight or branched chainsaturated hydrocarbon attached at two or more positions, such asmethylene (—CH₂—). Unless otherwise specified, the term “alkyl” mayinclude “alkylene” groups.

The term “alkylamino” as used herein, alone or in combination, refers toan alkyl group attached to the parent molecular moiety through an aminogroup. Suitable alkylamino groups may be mono- or dialkylated, forminggroups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene” as used herein, alone or in combination, refers toan alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(═O)—N(R)₂ group with R as defined herein. The term “N-amido” as usedherein, alone or in combination, refers to a RC(═O)N(R′)— group, with Rand R′ as defined herein. The term “acylamino” as used herein, alone orin combination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—N(R)(R′) or —N⁺(R)(R′)(R″), wherein R, R′ and R″ are independentlyselected from the group consisting of hydrogen, alkyl, acyl,heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any ofwhich may themselves be optionally substituted.

The term “amino acid” as used herein, alone or in combination, means asubstituent of the form —NRCH(R′)C(O)OH, wherein R is typicallyhydrogen, but may be cyclized with N (for example, as in the case of theamino acid proline), and R′ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl,arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol,thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionallysubstituted. The term “amino acid” includes all naturally occurringamino acids as well as synthetic analogues.

The term “aryl” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch rings may be attached together in a pendent manner or may be fused.The term “aryl” embraces aromatic radicals such as benzyl, phenyl,naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl,azulenyl, tetrahydronaphthyl, and biphenyl.

The term “arylalkenyl” or “aralkenyl” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl” as used herein, aloneor in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term “aryloxy” as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H₄ derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group—with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy” as used herein, refers to —C(O)OH,O-carboxy, C-carboxy, or the corresponding “carboxylate” anion, such asis in a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O—group, where R is as defined herein. A “C-carboxy” group refers to a—C(O)OR groups where R is as defined herein.

The term “cyano” as used herein, alone or in combination, refers to —CN.

The term “cycloalkyl” or, alternatively, “carbocycle” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from 3 to 12 carbon atom ring members and which mayoptionally be a benzo fused ring system which is optionally substitutedas defined herein. In certain embodiments, said cycloalkyl will comprisefrom 5 to 7 carbon atoms. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.“Bicyclic” and “tricyclic” as used herein are intended to include bothfused ring systems, such as decahydronaphthalene, octahydronaphthaleneas well as the multicyclic (multicentered) saturated or partiallyunsaturated type. The latter type of isomer is exemplified in generalby, bicyclo[1,1,1]pentane, camphor, adamantane, andbicyclo[3,2,1]octane.

The term “ester” as used herein, alone or in combination, refers to acarboxyl group bridging two moieties linked at carbon atoms.

The term “ether” as used herein, alone or in combination, typicallyrefers to an oxy group bridging two moieties linked at carbon atoms.“Ether” may also include polyethers, such as, for example,—RO(CH₂)₂O(CH₂)₂O(CH₂)₂OR′, —RO(CH₂)₂O(CH₂)₂OR′, —RO(CH₂)₂OR′, and—RO(CH₂)₂OH.

The term “halo” or “halogen” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy” as used herein, alone or in combination, refers toa haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon radical,or combinations thereof, fully saturated or containing from 1 to 3degrees of unsaturation, consisting of the stated number of carbon atomsand from one to three heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. The term “heteroalkyl” may include ethers.

The term “heteroaryl” as used herein, alone or in combination, refers to3 to 7 membered unsaturated heteromonocyclic rings, or fused polycyclicrings in which at least one of the fused rings is unsaturated, whereinat least one atom is selected from the group consisting of O, S, and N.In certain embodiments, said heteroaryl will comprise from 5 to 7 carbonatoms. The term also embraces fused polycyclic groups whereinheterocyclic radicals are fused with aryl radicals, wherein heteroarylradicals are fused with other heteroaryl radicals, or wherein heteroarylradicals are fused with cycloalkyl radicals. Examples of heteroarylgroups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl,benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl,benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl,benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl,tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclicheterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl,dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle” as usedherein, alone or in combination, each refer to a saturated, partiallyunsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclicheterocyclic radical containing at least one heteroatom as ring members,wherein each said heteroatom may be independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said heterocycloalkyl willcomprise from 1 to 2 heteroatoms ring members. In certain embodiments,said heterocycloalkyl will comprise from 3 to 8 ring members in eachring. In further embodiments, said heterocycloalkyl will comprise from 3to 7 ring members in each ring. In yet further embodiments, saidheterocycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sugars,sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, andcarbocyclic fused and benzo fused ring systems; additionally, both termsalso include systems where a heterocycle ring is fused to an aryl group,as defined herein, or an additional heterocycle group. Examples ofheterocycloalkyl groups include aziridinyl, azetidinyl,1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycloalkyl groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxamic acid” as used herein, refers to —C(O)ON(R)O(R′),wherein R and R′ are as defined herein, or the corresponding“hydroxamate” anion, including any corresponding hydroxamic acid salt.

The term “hydroxy” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino” as used herein, alone or in combination, refers to ═N—.

The term “iminohydroxy” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group. The phrase “linearchain of atoms” refers to the longest straight chain of atomsindependently selected from carbon, nitrogen, oxygen and sulfur.

The term “lower” as used herein, alone or in combination, meanscontaining from 1 to and including 6 carbon atoms.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa” as used herein, alone or in combination, referto —O—.

The term “oxo” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphoamide” as used herein, alone or in combination, refersto a phosphate group [(OH)₂P(O)O—] in which one or more of the hydroxylgroups has been replaced by nitrogen, amino, or amido.

The term “phosphonate” as used herein, alone or in combination, refersto a group of the form ROP(OR′)(OR)O—wherein R and R′ are selected fromthe group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl,cycloalkyl, heteroaryl, and heterocycloalkyl, any of which maythemselves be optionally substituted. “Phosphonate” includes “phosphate[(OH)₂P(O)O—] and related phosphoric acid anions which may form salts.

The terms “sulfonate”, “sulfonic acid” and “sulfonic,” as used herein,alone or in combination, refers to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl” as used herein, alone or in combination, refers to—S(O)₂-.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The terms “thia” and “thio” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂- group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl” as used herein, alone or in combination,refers to a silicone group substituted at its three free valences withgroups as listed herein under the definition of substituted amino.Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyland the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null” what is meant is that said group isabsent. A “null” group occurring between two other groups may also beunderstood to be a collapsing of flanking groups. For example, if in—(CH₂)G₁G2G₃, the element G₂ were null, said group would become—(CH₂)G₁G3.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term “R” or the term “R”, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may beoptionally substituted. Such R and R′ groups should be understood to beoptionally substituted as defined herein. Whether an R group has anumber designation or not, every R group, including R, R′ and R_(n)where n=(1, 2, 3, . . . n), every substituent, and every term should beunderstood to be independent of every other in terms of selection from agroup. Should any variable, substituent, or term (e.g. aryl,heterocycle, R, etc.) occur more than one time in a formula or genericstructure, its definition at each occurrence is independent of thedefinition at every other occurrence. Those of skill in the art willfurther recognize that certain groups may be attached to a parentmolecule or may occupy a position in a chain of elements from either endas written. Thus, by way of example only, an unsymmetrical group such as—C(O)N(R)— may be attached to the parent moiety at either the carbon orthe nitrogen.

Asymmetric centers exist in the compounds of the present invention.These centers are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds of the present invention may exist as geometric isomers. Thepresent invention includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers, including keto-enoltautomers; all tautomeric isomers are provided by this invention.Additionally, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the body or of one of its parts that impairs normalfunctioning and is typically manifested by distinguishing signs andsymptoms.

The term “apelin mediated disease or disorder” as used herein includesany disease or disorder that is mediated by apelin. Examples of apelinmediated diseases or disorders include, but are not limited to, acardiovascular disease or disorder, coronary heart disease, stroke,heart failure, systolic heart failure, diastolic heart failure, diabeticheart failure, heart failure with preserved ejection fraction,cardiomyopathy, myocardial infarction, left ventricular dysfunction,left ventricular dysfunction after myocardial infarction, cardiachypertrophy, myocardial remodeling, myocardial remodeling afterinfarction, myocardial remodeling after cardiac surgery, valvular heartdisease; a metabolic disease or disorder, metabolic syndrome, insulinresistance, diabetes mellitus, diabetic late complications, diabeticmacro- and micro-vasculopathies, diabetic nephropathy, diabeticretinopathy, diabetic neuropathies, cardiac autonomic neuropathy; adisease or disorder is caused by CNS-dependent or CNS-independentdisturbed fluid homeostasis, acute or chronic renal failure,hypertension, pulmonary hypertension, portal hypertension, systolichypertension; a vascular disease or disorder, vascular permeability,nonfunctional blood vessels, vascular hypertrophy, vascular remodeling,vascular stiffness, atherosclerosis, peripheral arterial occlusivedisease (PAOD), restenosis, thrombosis, vascular permeability disorders,ischemia, reperfusion damage, ischemia, reperfusion damage of the heart,kidney or retina, or a combination thereof.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain of the present compounds can also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound. The term “therapeutically acceptable prodrug” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use.

The compounds of the present invention can exist as therapeuticallyacceptable salts. The present invention includes compounds listed abovein the form of salts, including acid addition salts. Suitable saltsinclude those formed with both organic and inorganic acids. Such acidaddition salts will normally be pharmaceutically acceptable. However,salts of non-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002), the entire contents ofwhich are herein incorporated by reference.

The term “therapeutically acceptable salt” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible and therapeuticallyacceptable as defined herein. The salts can be prepared during the finalisolation and purification of the compounds or separately by reactingthe appropriate compound in the form of the free base with a suitableacid. Representative acid addition salts include acetate, adipate,alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds of the present invention can be quaternized withmethyl, ethyl, propyl, and butyl chlorides, bromides, and iodides;dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides; and benzyl andphenethyl bromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric. Salts can also beformed by coordination of the compounds with an alkali metal or alkalineearth ion. Hence, the present invention contemplates sodium, potassium,magnesium, and calcium salts of the compounds disclosed herein, and thelike.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxyl group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds of the present invention, or one or more pharmaceuticallyacceptable salts, esters, prodrugs, amides, or solvates thereof,together with one or more pharmaceutically acceptable carriers thereofand optionally one or more other therapeutic ingredients. The carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art; e.g.,in Remington's Pharmaceutical Sciences, the entire contents of which areincorporated herein by reference. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds of the present invention may be administeredtopically, that is by non-systemic administration. This includes theapplication of a compound of the present invention externally to theepidermis or the buccal cavity and the instillation of such a compoundinto the ear, eye and nose, such that the compound does notsignificantly enter the blood stream. In contrast, systemicadministration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, and cosmeticagents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as stearic or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as siliceous silicas, and otheringredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

In any case, the multiple therapeutic agents (at least one of which is acompound of the present invention) may be administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsmay be provided in a single, unified form, or in multiple forms (by wayof example only, either as a single pill or as two separate pills). Oneof the therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Administrations of apelins have been shown to cause vasodilatation indifferent pre-clinical models and accordingly, intravenousadministration in rodents reduces mean arterial blood pressure, systemicvenous tone and cardiac pre- and afterload. Vasodilatation to apelin inrodents is dependent on endothelium and mediated through nitric oxideand prostacyclin dependent pathways. Ishida and colleagues demonstratedin 2004, that a functional knockdown of the apelin receptor abolishedblood pressure lowering effects of apelins, confirming that vasculareffects of apelins are mediated by the apelin receptor specifically.

The vascular effects of apelin in preclinical studies translate intosimilar effects in humans. Infusions of apelins increased forearm andcoronary blood flow and lowered mean arterial pressure and peripheralvascular resistance in heart failure patients and healthy controlsubjects in heart failure patients without raising heart rates. Anincreased cardiac index could be noted, which may be explained by eitherdirect effects on the cardiac muscle (see below) and/or reduction ofpre- and afterload in the peripheral circulation. In man, vasodilatationby apelins is reduced by two thirds during nitric oxide synthaseinhibition but is unaffected by prostacyclin inhibition. The apelinreceptor has been linked to direct cardiac actions. In vitro, exogenousapelin increases contractility at subnanomolar concentrations in atrialstrips and whole rat hearts. In healthy rodents, acute apelin infusionincreases myocardial contractility independently of its effects onloading conditions. Uniquely among current inotropic agents, chronicdosing causes a sustained increase in cardiac output without inducingleft ventricular hypertrophy. While apelin-deficient mice display normalor only slightly impaired basal cardiac function at early life cycles,they demonstrate progressive cardiac dysfunction from 6 months of ageand develop severe heart failure when subjected to chronic pressureoverload.

Controversial results have been published regarding the involvement ofintracellular calcium on the contractility effects of apelin incardiomyocytes. Two groups described that intracellular calcium is not asignaling mechanism. However, others reported at least a modest increasein the amplitude of the intracellular calcium ion transients in failingrat trabeculae and isolated cardiomyocytes. Additionally, effects ofapelins in pre-clinical models have been described. Apelins may have animportant counter-regulatory role to vasopressin and hence fluidhomoeostasis. Apelin and the APJ receptor are both expressed also in thekidney and many areas of the brain. Synthesis in certain brain regionsinvolved in fluid homeostasis is regulated by vasopressin. To thecontrary, intracerebral injection of apelin directly inhibitsvasopressin release leading to a 40% reduction in plasma vasopressinconcentrations.

A link of apelins to metabolic syndrome is suggested by pre-clinicaldata. Apelins are produced by adipose tissue and may influence glucoseand lipid metabolism as adipocytokines. Acute intravenous administrationof pyf-apelin-13 stimulates glucose utilization in normal and obeseinsulin-resistant mice. These acute effects were explained by a directeffect of ¹pyr-apelin-13 on glucose uptake into skeletal muscle. Micedeficient for the apelins have reduced insulin sensitivity which can becorrected by sub-chronic supplementation with apelin via minipumps.Furthermore, in insulin resistant homozygous leptin receptor mutant mice(db/db mice) a similar sub-chronic administration results in improvedglucose utilization. Results with glucose utilization in apelin receptorknockout mice have not been published. Furthermore, it is not reportedyet, whether apelins significantly affect glucose handling in man.

The clinical and pre-clinical profile suggests applications of apelinreceptor agonists in different patient populations and indications. Inheart failure, apelins demonstrate a unique hemodynamic profile inenhancing myocardial contractility without inducing left ventricularhypertrophy. In parallel, ventricular pre- and afterload is reduced byreduced peripheral resistance. In pre-clinical models, apelin increasescontractility at least to the same extent in the failing compared tonormal myocardium. Irrespective of changes in receptor and ligandexpression, these studies indicate agonism of the receptor is notdiminished in situations of established heart failure. First data fromclinical studies with acute apelin infusions are promising. In contrastto acetylcholine, another vaso-active principle, vascular and cardiachemodynamic effects of apelins are preserved in chronic heart failurepatients. These patients received optimal pharmacological treatment,suggesting that the effects of apelin were additive to established heartfailure therapies like ACE-Inhibitors and/or β-blockers.

Regarding therapies targeting the diseased heart, acute beneficialeffects of apelins after acute myocardial infarction may be envisaged.It was shown that in preclinical models of acute myocardial ischemia andreperfusion administration of apelins at reperfusion strongly reducesmyocardial injury. However, opposing results regarding the underlyingsignaling of this cardioprotective mechanism have been reported. Onealternative is a mechanism based on activation of phosphatide-3-kinase,AKT kinase and P70S6 kinase. However, signaling pathways independent ofPI-3-kinase, AKT-kinase and p70S6 kinase may also explain the beneficialeffects of apelin receptor agonists in ischemia-reperfusion injury.Apelin increases both phosphorylation and activity of key componentswithin reperfusion injury salvage kinase pathway. This pro-survivalpathway is known to be associated with reducedischemia-reperfusion-injury by preserving mitochondrial function.Despite the fact, preconditioning agents are difficult to implement inclinical practice, apelin receptor agonists may be administered with thereperfusion solution directly after acute myocardial infarction andthereby display potential benefits in both restoring cardiac survivaland function. Another application, especially of oral bioavailable smallmolecule apelin receptor agonists, could be to start in a patient withan acute myocardial infarction with an intravenous formulation duringreperfusion and continue later, e.g., outside the clinic, with an oralbioavailable formulation of the same drug component. Furthermore,intravenous or oral administration of apelin receptor agonists could beenvisaged in patients with acute heart failure. Very often acute heartfailure develops in the progression of chronic heart failurespontaneously as acute episodes of disease worsening but without signsof myocardial infarction. Patients are then hospitalized and stabilizedduring hospitalization by agents increasing the contractility of thedisease heart muscle. Apelin receptor agonists display a uniquehemodynamic profile suggesting a safe and efficient use in suchpatients.

Agonists of the apelin receptor may also represent a novel class ofanti-hypertensive agents. In preclinical models, administration ofapelin peptides lowers blood pressure, greatly enhanced in hypertensiveanimals compared with normotensive controls. In first clinical studiesmodest but significant effects on blood pressure lowering could bedemonstrated in normotensive middle-aged subjects. Whether intravenouslyapplied apelin peptides lower blood pressure stronger in hypertensivepatient populations, similar to the situation in normotensive vs.hypertensive rats, needs to be evaluated. Application of apelin peptidesin hypertensive patients is strongly limited by the need of intravenousadministration route. However, small molecule apelin receptor agonistsas claimed in this patent application may have a much wider applicationin these patients due to better oral bioavailability.

Apelin receptor agonists appear to have beneficial effects on additionalvascular based diseases. In atherosclerotic mice deficient for theApolipoprotein-E, apelin infusion inhibits atherosclerosis progress andcompletely abrogates angiotensin II-accelerated detrimental effectsindependent of blood pressure. And in double knockout mice, deficient infor the apelin receptor ligand and Apolipoprotein-E, acceleratedatherosclerosis could be observed compared versus singleApolipoprotein-E-knockout. Pro-atherosclerotic effects of the apelinreceptor have also been described in a combined mice knockout-model ofthe apelin receptor and apolipoprotein-E ApoE. Overall these results aredifficult to reconcile. Most probably very different fat feedingregimens or different genetic backgrounds and so called off-targetgenetic effects best explain the observed differences. Independent ofeffects on atherosclerosis progression, apelin treatment resulted inreduced aneurysm by 50% in a mouse model of abdominal aortic aneurysms,an effect explained by the authors by a direct anti-inflammatory effectwithin the vessel wall.

Furthermore, apelin receptor agonists may play an important role inmaturation of newly formed blood vessels. It was described in a model ofvascular remodeling after hind limb ischemia in mice, that apelinsinduce the maturation into enlarged and non-leaky blood vessels forfunctional recovery. Especially pathologically increased vascularpermeability induced by VEGF under hypoxic conditions seems to becorrected by apelins.

In humans, apelins cause nitric oxide-mediated vasodilatation in forearmresistance vessels of healthy subjects. Based on promising preclinicaldata, the role of apelin receptor agonists in preventing human vasculardisease merits further investigations. These investigations will bestrongly facilitated by small molecule apelin receptor agonists, asclaimed in this patent application, because the oral bioavailabilityallows for much easier chronic administration routes.

In patients with metabolic syndrome and diabetes, apelin receptoragonists may provide additional benefits. Apelins are produced also byadipose tissue and influence glucose and lipid metabolism asadipocytokines. Mice with no apelin receptor ligands have reducedinsulin sensitivity which can be corrected by the administration ofexogenous apelin. Acute and sub-chronic positive effects of apelins onglucose utilizations following a glucose load have been described ininsulin-resistant animal strains. Although the translation of theseeffects to man needs to be performed, apelin receptor agonists may offeradditional therapeutic options especially in insulin-resistant patients,insufficiently dealing with increased plasma glucose load in metabolicsyndrome and diabetes. The simultaneous beneficial effects on bloodglucose lowering and vascular and cardiac homeostasis are a uniqueadvantage to therapeutic principles affecting blood glucose alone andopen an avenue to macro- and microvascular diabetic late complications,like diabetic cardiomyopathies, diabetic retinopathy, diabetic macularedema, diabetic nephropathy and diabetic neuropathy. Oral bioavailablesmall molecule apelin receptor agonist would strongly boost these areasof applications because they would be not restricted to intravenous orsubcutaneous administration routes.

There continues to be a need for further effective low molecular weightAPJ modulators, in particular in view of safety and selectivity. Thecompounds disclosed herein are selective for the apelin receptor, andhave been shown to be highly specific for the apelin receptor versus theangiotensin II receptor (AT1), the most closely related receptor. Broadselectivity profiling experiments revealed no significant off targetbinding. The compounds disclosed herein show favorable in vitroabsorption, distribution, metabolism, and excretion (ADME) propertiesand excellent in vivo pharmacokinetics. The compounds of the presentdisclosure are contemplated to be useful as novel therapies for thetreatment for a range of cardiovascular, renal and metabolic conditions.

The following examples are intended to illustrate but not limit theinvention.

EXPERIMENTAL METHODS

7-Isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Amide Step 1

To a solution of phenyl-acetonitrile (11.7 g, 100 mmol) in THF (200 mL)was added NaH (12.4 g, 310 mmol), followed by EtOAc (35.2 g, 400 mmol),and the resulting mixture was stirred at room temperature overnight. TLCshowed the SM was consumed. The reaction was quenched with 1 M HCl (300mL), and the resulting mixture was extracted with EtOAc (200 mL×2). Thecombined organic layers were washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by column chromatography on silica gel (PE/EtOAc=10/1) toafford the desired 3-oxo-2-phenyl-butyronitrile (13 g, yield: 82%) as awhite solid.

Step 2

A mixture of 3-oxo-2-phenyl-butyronitrile (13 g, 81.67 mmol) andN₂H₄.H₂O (8.8 mL) in EtOH (150 mL) was heated to 80° C. overnight, andLCMS showed the reaction was completed. The reaction mixture wasconcentrated, and the residue was diluted with brine (100 mL). Themixture was extracted with EtOAc (100 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was triturated with hexane to afford the desired5-methyl-4-phenyl-1H-pyrazol-3-ylamine (3.2 g, yield: 23%) as anoff-white solid.

¹HNMR (400 MHz, CDCl₃): δ=7.43-7.24 (m, 5H), 5.48 (brs, 2H), 2.28 (s,3H).

Step 3

A mixture of 5-methyl-4-phenyl-1H-pyrazol-3-ylamine (600 mg, 3.46 mmol)and 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (677 mg, 3.64 mmol) inMeOH (50 mL) was heated to 80° C. for overnight, and LCMS showed thereaction was completed. The reaction mixture was concentrated to givethe crude product which was purified by column chromatography on silicagel (PE/EtOAc=10/1) to afford the desired7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (580 mg, yield: 52%) as a yellow solid.

¹HNMR (400 MHz, CDCl₃): δ=7.78 (d, J=7.6 Hz, 2H), 7.48 (t, J=7.6 Hz,2H), 7.39 (s, 1H), 7.37-7.33 (m, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.98-3.91(m, 1H), 2.70 (s, 3H), 1.49 (d, J=6.4 Hz, 6H), 1.45 (t, J=7.2 Hz, 3H).

Step 4

To a solution of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (580 mg, 1.80 mmol) in dioxane (40 mL) was added 0.5 MLiOH.H₂O (8.0 mL, 3.60 mmol), and the resulting mixture was stirred atroom temperature overnight. TLC showed the reaction was completed. Thereaction mixture was concentrated, and the residue was diluted withwater (50 mL). The mixture was adjusted to pH=4.0. The resulting mixturewas extracted with EtOAc (50 mL×3), and the combined organic layers weredried over Na₂SO₄, filtered and concentrated to give the desired7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (530 mg, yield: 99%) as a yellow solid.

Step 5

To a solution of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (50 mg, 0.17 mmol) in oxalyl chloride (10 mL) was added NH₃ (THFsolution) (3 mL). The solution was stirred at room temperatureovernight. THF and oxalyl chloride was removed. The residue was purifiedby prep-HPLC (ACN/NH₃H₂O) to afford7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide (20 mg, yield: 40%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.75-7.73 (m, 2H), 7.54-7.48 (m, 3H),7.37-7.34 (m, 1H), 3.96-3.80 (m, 1H), 2.67 (s, 3H), 1.50 (d, J=9.2 Hz,6H). MS: m/z 294.9 (M+H⁺)

7-Isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methylamide

To a solution of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (50 mg, 0.17 mmol) in DMF (10 mL) was added HATU (97 mg, 0.25 mmol)and DIPEA (88 mg, 0.68 mmol). The solution was stirred at roomtemperature for 30 min. Then to the mixture was added methylaminehydrochloride (13 mg, 0.19 mmol) and the mixture was stirred overnight.DMF was removed and the residue was treated with water (15 mL). Theaqueous phase was extracted with EtOAc (10 mL×3). The organic layer waswashed with brine (20 mL), dried and concentrated. The residue waspurified by prep-HPLC (ACN/NH₃H₂O) to afford7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide (20 mg, yield: 40%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d₆): δ=8.57-8.56 (m, 1H), 7.82-7.80 (m, 2H), 7.50(t, J=7.6 Hz, 2H), 7.42 (s, 1H), 7.37-7.34 (m, 1H), 3.85-3.81 (m, 1H),2.85 (s, 3H), 2.62 (s, 3H), 1.42 (d, J=7.2 Hz, 6H). MS: m/z 308.9(M+H⁺).

7-Isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Dimethylamide

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methylamide.

¹HNMR (300 MHz, CD₃OD): δ=7.72-7.69 (m, 2H), 7.54-7.48 (m, 2H),7.37-7.34 (m, 1H), 7.05 (s, 1H), 3.96-3.80 (m, 1H), 3.20-3.12 (d, J=7.6Hz, 6H), 2.67 (s, 3H), 1.30 (d, J=7.2 Hz, 6H). MS: m/z 322.9 (M+H⁺).

[(7-Isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carbonyl)-amino]-aceticAcid Step 1

To a solution of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (50 mg, 0.17 mmol) in oxalyl chloride (10 mL) was addedamino-acetic acid ethyl ester (24 mg, 0.17 mmol). The solution wasstirred at room temperature overnight. THF and oxalyl chloride wasremoved. The residue was purified by prep-HPLC (ACN/NH₃H₂O) to afford[(7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carbonyl)-amino]-aceticacid ethyl ester (32.4 mg, yield: 50%) as a yellow solid.

Step 2

To a solution of[(7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carbonyl)-amino]-aceticacid ethyl ester (32.4 mg, 0.0852 mmol) in THF/H₂O (10 mL) was addedLiOH (11 mg, 0.255 mmol), and the reaction solution was stirred at roomtemperature overnight. The reaction mixture was evaporated to remove thesolvent. The residue was acidified with dilute HCl till pH=3-4. Theresulting solid was filtered to afford[(7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carbonyl)-amino]-aceticacid (25 mg, yield: 83%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.77 (d, J=7.2 Hz, 2H), 7.55 (s, 1H), 7.52 (t,J=7.6 Hz, 2H), 7.36 (t, J=7.2 Hz, 1H), 4.17 (s, 2H), 3.96-3.80 (m, 1H),2.67 (s, 3H), 1.52 (d, J=7.2 Hz, 6H). MS: m/z 352.9 (M+H⁺).

3-(2-Fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a solution of (2-fluoro-phenyl)-acetonitrile (1.50 g, 11.1 mmol) andEtOAc (4.4 mL, 44.4 mmol) in THF (20 mL) was added NaH (0.90 g, 22.2mmol). The mixture was stirred at room temperature overnight. Then thereaction mixture was acidified to pH=6 with HCl (1 mol/L) and extractedwith EtOAc (10 mL×3). The combined organic layer was washed with brine(20 mL), dried with Na₂SO₄ and concentrated to dryness in vacuum. Theresidue was purified by silica gel column chromatography (PE/EtOAc=2/1)to afford 2-(2-fluoro-phenyl)-3-oxo-butyronitrile (1.48 g, yield: 76%)as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆): δ=11.46 (brs, 1H), 7.42-7.35 (m, 2H),7.31-7.16 (m, 2H), 2.29 (s, 3H).

Step 2

To a solution of 2-(2-fluoro-phenyl)-3-oxo-butyronitrile (1.50 g, 8.47mmol) in EtOH (20 mL) was added hydrazine monohydrochloride (1.28 g,18.64 mmol), and the solution was stirred at 80° C. overnight. Then thereaction mixture was evaporated and the residue was dissolved in EtOAc(20 mL). The solution was washed with saturated NaHCO₃ solution (20 mL),followed with brine (20 mL), dried and concentrated. The residue waspurified by silica gel column chromatography (DCM/MeOH=40/1) to afford4-(2-fluoro-phenyl)-5-methyl-1H-pyrazol-3-ylamine (1.20 g, yield: 75%)as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆): δ=7.37-7.28 (m, 2H), 7.25-7.18 (m, 2H), 4.40(s, 2H), 2.05 (s, 3H).

Step 3

To a solution of 4-(2-fluoro-phenyl)-5-methyl-1H-pyrazol-3-ylamine (300mg, 1.56 mmol) and 2,4-dioxo-hexanoic acid ethyl ester (324 mg, 1.74mmol) in EtOH (10 mL) was stirred at 80° C. overnight. The reactionmixture was evaporated to dryness in vacuum. The residue was purified bysilica gel column chromatography (PE/EtOAc=20/1) to afford3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (350 mg, yield: 66%) as a yellow solid.

¹HNMR (300 MHz, DMSO-d₆): δ=7.56 (t, J=7.5 Hz, 1H), 7.48 (t, J=7.5 Hz,1H), 7.41-7.32 (m, 3H), 4.36 (q, J=7.2 Hz, 2H), 3.87-3.82 (m, 1H), 2.45(s, 3H), 1.43 (d, J=7.2 Hz, 6H), 1.32 (t, J=7.2 Hz, 3H). MS: m/z 342.1(M+H⁺).

Step 4

To a solution of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (200 mg, 0.59 mmol) in THF/H₂O (10 mL) was added LiOH(74 mg, 1.76 mmol), and the reaction solution was stirred at roomtemperature overnight. The reaction mixture was evaporated to remove thesolvent. The residue was acidified with dilute HCl till pH=3-4. Theresulting solid was filtered to afford3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (128 mg, yield: 69%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.62-7.58 (m, 1H), 7.52 (s, 1H), 7.45-7.42 (m,1H), 7.32-7.24 (m, 2H), 3.96 (m, 1H), 2.52 (s, 3H), 1.53 (d, J=7.2 Hz,6H). MS: m/z 314.1 (M+H⁺).

7-Isopropyl-2-methyl-3-o-tolyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.49 (s, 1H), 7.37-7.28 (m, 4H), 4.02-3.85 (m,1H), 2.44 (s, 3H), 2.17 (s, 3H), 1.53 (d, J=7.2 Hz, 6H). MS: m/z 309.9(M+H⁺).

3-(2-Methoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.44-7.39 (m, 1H), 7.35-7.33 (m, 2H),7.18-7.16 (m, 1H), 7.09-7.05 (m, 1H), 4.36 (q, J=6.8 Hz, 2H), 3.85-3.82(m, 1H), 3.79 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.8 Hz, 6H), 1.31 (t,J=6.9 Hz, 3H). MS: m/z 354 (M+H⁺).

3-(2-Methoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.44-7.37 (m, 3H), 7.12-7.04 (m, 2H),3.93-3.90 (m, 1H), 3.79 (s, 3H), 2.42 (s, 3H), 1.49 (d, J=6.8 Hz, 6H).MS: m/z 324.1 (M−H⁺).

3-(2-Chloro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.89 (t, J=4.0 Hz, 1H), 7.43 (d, J=7.6 Hz,1H), 7.50-7.46 (m, 2H), 7.37-7.34 (m, 1H), 4.51-4.46 (m, 2H), 3.96-3.92(m, 1H), 2.70 (s, 3H), 1.50 (d, J=8.0 Hz, 6H), 1.32 (t, J=7.6 Hz, 3H).MS: m/z 358.1 (M+H⁺).

3-(2-Chloro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid

¹HNMR (400 MHz, CD₃OD): δ=7.80 (s, 1H), 7.72 (d, J=7.6 Hz, 1H),7.50-7.43 (m, 2H), 7.33-7.31 (m, 1H), 3.96-3.92 (m, 1H), 2.66 (s, 3H),1.50 (d, J=7.2 Hz, 6H). MS: m/z 330.1 (M+H⁺).

7-Isopropyl-2-methyl-3-m-tolyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (300 MHz, CD₃OD): δ=7.58 (s, 1H), 7.51 (d, J=6.3 Hz, 1H), 7.44 (s,1H), 7.36 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 4.50-4.42 (m, 2H),3.91-3.89 (m, 1H), 2.65 (s, 3H), 2.44 (s, 3H), 1.50 (d, J=6.9 Hz, 6H),1.46-1.41 (t, J=7.2 Hz, 3H). MS: m/z 337.9 (M+H⁺).

7-Isopropyl-2-methyl-3-m-tolyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.46 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.37 (s,1H), 7.26 (t, J=7.2 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 3.83-3.80 (m, 1H),2.54 (s, 3H), 2.33 (s, 3H), 1.40 (d, J=6.8 Hz, 6H). MS: m/z 309.9(M+H⁺).

7-Isopropyl-3-(3-methoxy-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.49-7.45 (m, 2H), 7.42-7.37 (m, 1H),7.33-7.31 (m, 1H), 6.93-6.91 (m, 1H), 4.50-4.44 (m, 2H), 3.94-3.89 (m,4H), 2.68 (s, 3H), 1.50 (d, J=8.0 Hz, 6H), 1.32 (t, J=7.6 Hz, 3H). MS:m/z 354.1 (M+H⁺).

7-Isopropyl-3-(3-methoxy-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.47 (s, 1H), 7.40-7.36 (m, 2H), 7.31-7.30 (m,1H), 6.91-6.88 (m, 1H), 3.92-3.89 (m, 1H), 3.86 (s, 3H), 2.66 (s, 3H),1.49 (d, J=6.8 Hz, 6H). MS: m/z 326.1 (M+H⁺).

3-(3-Fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid

¹HNMR (400 MHz, DMSO-d₆): δ=7.66-7.54 (m, 3H), 7.42 (s, 1H), 7.20-7.18(m, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.84 (q, J=6.8 Hz, 1H), 2.66 (s, 3H),1.42 (d, J=7.2 Hz, 6H), 1.36 (t, J=6.8 Hz, 3H). MS: m/z 342.1 (M+H⁺).

3-(3-Fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.52-7.39 (m, 2H), 7.36-7.33 (m, 2H),6.95-6.90 (m, 1H), 3.79 (q, J=6.8 Hz, 1H), 2.56 (s, 3H), 1.38 (d, J=6.8Hz, 6H). MS: m/z 312 (M−H⁺).

3-(3-Chloro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.90 (s, 1H), 7.72-7.69 (m, 1H), 7.56-7.51(m, 1H), 7.42-7.39 (m, 2H), 4.42 (q, J=6.9 Hz, 2H), 3.83 (q, J=6.9 Hz,1H), 2.65 (s, 3H), 1.47 (d, J=6.9 Hz, 6H), 1.36 (t, J=6.8 Hz, 3H). MS:m/z 358.1 (M+H⁺).

3-(3-Chloro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.69-7.63 (m, 2H), 7.36-7.31 (m, 2H),7.20-7.18 (m, 1H), 3.78 (q, J=6.8 Hz, 1H), 2.54 (s, 3H), 1.38 (d, J=6.8Hz, 6H). MS: m/z 328.1 (M−H⁺).

3-(2-Fluoro-6-methoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.42-7.40 (m, 2H), 6.94 (d, J=8.0 Hz, 1H),6.84 (t, J=8.0 Hz, 1H), 4.42-4.39 (m, 2H), 3.96-3.92 (m, 1H), 3.77 (s,3H), 2.37 (s, 3H), 1.50 (d, J=6.8 Hz, 6H), 1.38 (t, J=6.8 Hz, 3H). MS:m/z 372.1 (M+H⁺).

3-(2-Fluoro-6-methoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.47-7.40 (m, 1H), 7.30 (s, 1H), 6.98 (d,J=8.8 Hz, 1H), 6.93 (t, J=8.0 Hz, 1H), 3.76 (s, 3H), 3.08-3.04 (m, 1H),2.27 (s, 3H), 1.22 (d, J=6.8 Hz, 6H). MS: m/z 344.0 (M+H⁺).

3-(2,4-Dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a solution of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (120 mg, 0.367 mmol) and (2,4-dimethylphenyl)boronic acid(77 mg, 0.514 mmol), K₃PO₄ (311 mg, 1.47 mmol) in toluene (5 mL) wasadded Pd(PPh₃)₄ (48 mg). The vial was purged with nitrogen for a minute.The mixture was heated to 160° C. by microwave for 3 hrs. The solutionwas removed under reduced pressure. The residue was purified by silicagel column to give3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (100 mg, yield: 77%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.42 (s, 1H), 7.20-7.12 (m, 3H), 4.42-4.38 (m,2H), 3.96-3.82 (m, 1H), 2.38 (d, J=8.4 Hz, 6H), 2.10 (s, 3H), 1.50 (d,J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). MS: m/z 352.2 (M+H⁺).

Step 2

To a solution of3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (100 mg, 0.285 mmol) in THF/H₂O (8 mL/2 mL) was addedLiOH (40 mg, 0.95 mmol), and the reaction solution was stirred at roomtemperature overnight. The reaction mixture was evaporated to remove thesolvent. The residue was acidified with dilute HCl till pH=3-4. Theresulting solid was filtered to afford3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (10 mg, yield: 23%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.46 (s, 1H), 7.22-7.12 (m, 3H), 3.96-3.82 (m,1H), 2.40-2.37 (m, 6H), 2.11 (s, 3H), 1.50 (d, J=6.8 Hz, 6H). MS: m/z324.2 (M+H⁺).

3-(2,6-Dimethoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.42-7.33 (m, 2H), 6.76 (d, J=8.8 Hz, 2H),4.39 (q, J=7.2 Hz, 2H), 3.92-3.88 (m, 1H), 3.71 (s, 6H), 2.31 (s, 3H),1.51 (d, J=6.8 Hz, 6H), 1.37 (t, J=8.8 Hz, 3H). MS: m/z 384.0 (M+H⁺).

3-(2,6-Dimethoxy-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.49 (s, 1H), 7.28-7.12 (m, 3H), 3.91-3.86 (m,1H), 2.30 (s, 3H), 2.02 (s, 6H), 1.53 (d, J=_6.8 Hz, 6H). MS: m/z 356.2(M+H⁺).

3-(2-Ethoxycarbonyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.78 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz,1H), 7.45 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 4.43-4.37 (m, 2H), 3.96-3.82(m, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.50 (d, J=7.2 Hz, 6H), 1.36 (t,J=7.2 Hz, 3H), 0.83 (t, J=7.2 Hz, 3H). MS: m/z 410.2 (M+H⁺).

3-(2-Ethoxycarbonyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,4-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.77 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz,1H), 7.46-7.42 (m, 2H), 3.96-3.92 (m, 3H), 2.28 (s, 3H), 2.09 (s, 3H),1.51 (d, J=6.0 Hz, 6H), 0.83 (t, J=6.8 Hz, 3H). MS: m/z 382.1 (M+H⁺)

3-(2-Fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a solution of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (500 mg, 1.53 mmol) and bis(pinacolato)diboron (584 mg, 2.30mmol) in dioxane (10 mL) were added Pd(PPh₃)₂Cl₂ (112 mg, 0.153 mmol)and KOAc (450 mg, 4.6 mmol). The resulting mixture was bubbled with N₂for 5 mins and stirred at 110° C. irradiated by microwave for 2 hrs.Then the reaction mixture was filtered, and the filtrate wasconcentrated in vacuum to give a residue, which was purified by areversed-phase column (B from 5-95, A: H₂O, B: ACN) to afford7-isopropyl-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (124 mg, yield: 22%) as a yellow solid.

Step 2

To a solution of7-isopropyl-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (120 mg, 0.32 mmol) and2-bromo-1-fluoro-3-methyl-benzene (60.8 mg, 0.322 mmol) in toluene (3mL) were added Pd(PPh₃)₄ (37.2 mg, 0.032 mmol) and K₃PO₄ (273.4 mg, 1.28mmol). The resulting mixture was bubbled with N₂ for 5 mins and stirredat 130° C. irradiated by microwave for 2 hrs. Then the reaction mixturewas filtered, and the filtrate was concentrated in vacuum to give aresidue, which was purified by a reversed-phase column (B from 5-95, A:H₂O, B: ACN) to afford3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (30.0 mg, yield: 26%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.46 (s, 1H), 7.37-7.31 (m, 1H), 7.18 (d,J=7.6 Hz, 1H), 7.04 (t, J=8.8 Hz, 1H), 4.44-4.39 (m, 2H), 3.96-3.92 (m,1H), 2.37 (s, 3H), 2.14 (s, 3H), 1.51 (d, J=6.8 Hz, 6H), 1.38 (t, J=7.2Hz, 3H). MS: m/z 356.2 (M+H⁺).

Step 3

To a solution of3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (30.0 mg, 0.084 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (10.6 mg, 0.25 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to Ph=3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2) and the combined organic layers wereconcentrated in vacuum to afford3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (27.0 mg, yield: 98%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.49 (s, 1H), 7.35-7.31 (m, 1H), 7.16 (d,J=8.8 Hz, 1H), 7.02 (t, J=8.8 Hz, 1H), 3.94-3.90 (m, 1H), 2.36 (s, 3H),2.14 (s, 3H), 1.51 (d, J=6.8 Hz, 6H). MS: m/z 328.1 (M+H⁺).

3-(2,6-Diethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.33-7.31 (m, 2H), 7.22-7.19 (m, 2H),3.89-3.79 (m, 1H), 2.30-2.10 (m, 7H), 1.42 (d, J=7.2 Hz, 6H), 0.89 (t,J=7.6 Hz, 6H). MS: m/z 352.1 (M+H⁺).

3-(2-Ethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.47 (s, 1H), 7.25-7.23 (m, 1H), 7.19-7.14(m, 2H), 3.89-3.79 (m, 1H), 2.32-2.27 (m, 5H), 1.95 (s, 3H), 1.52 (d,J=7.2 Hz, 6H), 0.93 (t, J=7.6 Hz, 3H). MS: m/z 338.1 (M+H⁺).

7-Isopropyl-3-(2-methoxy-6-methyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.40 (s, 1H), 7.32-7.27 (m, 1H), 6.96-6.91 (m,2H), 4.42-4.38 (m, 2H), 3.96-3.82 (m, 1H), 3.69 (s, 3H), 2.30 (s, 3H),2.03 (s, 3H), 1.50 (d, J=7.2 Hz, 6H), 1.36 (t, J=7.6 Hz, 3H). MS: m/z368.2 (M+H⁺).

7-Isopropyl-3-(2-methoxy-6-methyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2-fluoro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.44 (s, 1H), 7.30 (t, J=8.0 Hz, 1H),6.96-6.89 (m, 2H), 3.93-3.90 (m, 1H), 3.69 (brs, 3H), 2.28 (s, 3H), 2.02(brs, 3H), 1.51 (d, J=6.8 Hz, 6H). MS: m/z 340.1 (M+H⁺).

Step 13-(2-Hydroxymethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[11,5-a]pyrimidine-5-carboxylicAcid

To a solution of 2-bromo-3-methyl-benzoic acid (4.5 g, 20.9 mmol) inEtOH (60 mL) was added conc. H₂SO₄ (6 mL). The resulting mixture wasstirred at 80° C. overnight. The reaction was monitored by TLC. ThenEtOH was removed in vacuum to give a residue, which was diluted with H₂O(60 mL). The mixture was extracted with DCM (60 mL×2). The combinedorganic layers were concentrated to give a crude product, which waspurified by a silica gel column (DCM) to afford 2-bromo-3-methyl-benzoicacid ethyl ester (4.96 g, yield: 97%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=7.44 (dd, J=7.6, 1.2 Hz, 1H), 7.33 (d, J 7.6,0.8 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 2.46 (s,3H), 1.40 (t, J 7.2 Hz, 3H).

Step 2

To a solution of 2-bromo-3-methyl-benzoic acid ethyl ester (1.6 g, 6.58mmol) in dry THF (20 mL) was added LiBH₄ (3.29 mL, 2 M in THF) at 0° C.The resulting mixture was allowed to warm to room temperature andstirred overnight. Then the reaction was quenched by slow addition ofH₂O (10 mL) at 0° C. The mixture was extracted with EtOAc (20 mL×3) andthe combined organic layers were concentrated in vacuum to afford(2-bromo-3-methyl-phenyl)-methanol (1.26 g, yield: 95%).

¹H NMR (400 MHz, DMSO-d6): δ=7.37 (d, J=6.4 Hz, 1H), 7.28 (t, J=7.2 Hz,1H), 7.23 (d, J=6.8 Hz, 1H), 5.39 (brs, 1H), 4.52 (s, 2H), 2.36 (s, 3H).

Step 3

To a solution of (2-bromo-3-methyl-phenyl)-methanol (1.0 g, 4.97 mmol)in dry THF (40 mL) was added NaH (400 mg, 4.97 mmol, 60% wt) at 0° C.The mixture was stirred at 0° C. for 1 hr. Then Mel (706 mg, 4.97 mmol)was added into the reaction mixture. The resulting mixture was stirredat room temperature for another 1 hr. The reaction was monitored by TLC.Then the mixture was poured into ice-water (40 mL) and extracted withDCM (20 mL×3). The combined organic layers were concentrated in vacuumto give a residue, which was purified by a silica gel column (DCM) toafford 2-bromo-1-methoxymethyl-3-methyl-benzene (988 mg, yield: 92%) asa colorless oil.

Step 4

To a solution of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (500 mg, 1.53 mmol) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (584 mg,2.30 mmol) in dioxane (10 mL) were added Pd(PPh₃)₂Cl₂ (112 mg, 0.153mmol) and KOAc (450 mg, 4.6 mmol). The resulting mixture was bubbledwith N₂ for 5 mins and stirred at 110° C. irradiated by microwave for 2hrs. Then the reaction mixture was filtered, and the filtrate wasconcentrated in vacuum to give a residue, which was purified by areversed-phase column (B from 5-95, A: H₂O, B: ACN) to afford7-isopropyl-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (124 mg, yield: 22%) as a yellow solid.

Step 5

To a solution of7-isopropyl-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (150 mg, 0.401 mmol) and(2-bromo-3-methyl-phenyl)-methanol (121 mg, 0.602 mmol) in toluene (8mL) were added Pd(PPh₃)₄ (46.3 mg, 0.0401 mmol) and K₃PO₄ (255 mg, 1.203mmol). The resulting mixture was bubbled with N₂ for 5 mins and stirredat 130° C. irradiated by microwave for 2 hrs. Then the reaction mixturewas filtered, and the filtrate was concentrated in vacuum to give aresidue, which was purified by a reversed-phase column (B from 5-95, A:H₂O, B: ACN) to afford3-(2-hydroxymethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (32.4 mg, yield: 22%) as a yellow solid.

Step 6

To a solution of3-(2-hydroxymethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (32.4 mg, 0.088 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (15 mg, 0.35 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH 3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2) and the combined organic layers wereconcentrated in vacuum to afford3-(2-hydroxymethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (21.6 mg, yield: 72%) as a yellow solid.

¹H NMR (400 MHz, CD₃OD): δ=7.51-7.43 (m, 2H), 7.36 (t. J=7.6 Hz, 1H),7.28 (t, J=7.2 Hz, 1H), 4.32-4.20 (m, 2H), 4.00-3.90 (m, 1H), 3.31 (s,3H), 2.00 (s, 3H), 1.51 (d, J=7.2 Hz, 6H). MS: m/z 339.9 (M+H⁺).

7-Isopropyl-3-(2-methoxymethyl-6-methyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared as described in example3-(2-hydroxymethyl-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹H NMR (400 MHz, DMSO-d6): δ=7.52-7.26 (m, 4H), 4.05 (d, J=12.4 Hz, 1H),4.01 (d, J=12.4 Hz, 1H), 3.92-3.82 (m, 1H), 3.09 (s, 3H), 2.25 (s, 3H),1.95 (s, 3H), 1.45 (d, J=5.2 Hz, 6H). MS: m/z 353.9 (M+H⁺).

3-(2-Carboxy-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

A mixture of 5-methyl-2H-pyrazol-3-ylamine (1.8 g, 18.5 mmol) and5-methyl-2,4-dioxo-hexanoic acid ethyl ester (3.8 g, 20.4 mmol) in EtOH(40 mL) was stirred at 80° C. overnight. The reaction was monitored byLCMS. Then EtOH was removed in vacuum to give a crude product, which waspurified by a silica gel column (DCM/MeOH=200/1) to afford7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethylester (2.66 g, yield: 58%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.38 (s, 1H), 6.72 (s, 1H), 4.52 (q, J=7.2Hz, 2H), 3.97-3.86 (m, 1H), 2.57 (s, 3H), 1.50-1.43 (m, 9H).

Step 2

To a solution of7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethylester (4.6 g, 18.6 mmol) in CCl₄ (60 mL) was added NBS (3.97 g, 22.3mmol). The resulting mixture was stirred at 80° C. for 2 hrs. Thereaction was monitored by LCMS. Then CCl₄ was removed in vacuum to givea residue, which was purified by a silica gel column with (DCM) toafford3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (6.04 g, yield: 99%) as a yellow solid.

¹HNMR (400 MHz, CDCl₃): δ=7.40 (s, 1H), 4.51 (q, J=7.2 Hz, 2H),3.95-3.83 (m, 1H), 2.56 (s, 3H), 1.51-1.43 (m, 9H). MS: m/z 324.0(M+H⁺).

Step 3

To a solution of 2-bromo-3-methyl-benzoic acid (4.5 g, 20.9 mmol) inEtOH (60 mL) was added conc. H₂SO₄ (6 mL). The resulting mixture wasstirred at 80° C. overnight. The reaction was monitored by TLC. ThenEtOH was removed in vacuum to give a residue, which was mixed with H₂O(60 mL) and extracted with DCM (60 mL×2). The combined organic layerswere concentrated to give a crude product, which was purified by asilica gel column (DCM) to afford 2-bromo-3-methyl-benzoic acid ethylester (4.96 g, yield: 97%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=7.44 (dd, J=7.6, 1.2 Hz, 1H), 7.33 (d, J=7.6,0.8 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 2.46 (s,3H), 1.40 (t, J=7.2 Hz, 3H).

Step 4

To a solution of 2-bromo-3-methyl-benzoic acid ethyl ester (500 mg, 2.06mmol) and 4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](784 mg, 3.08 mmol) in dioxane/H₂O (40 mL+5 mL) were added Pd(dppf)Cl₂(150 mg, 0.206 mmol) and KOAc (868 mg, 8.84 mmol). The resulting mixturewas degassed and refilled with N₂ for 3 times and stirred at 90° C.under N₂ atmosphere overnight. Then the reaction mixture was filtered,and the filtrate was concentrated in vacuum to give a residue, which waspurified by a silica gel column (DCM) to afford3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidethyl ester (426 mg, yield: 72%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=7.77 (dd, J=7.2, 0.8 Hz, 1H), 7.33-7.23 (m,2H), 4.36 (q, J=7.2 Hz, 2H), 2.44 (s, 3H), 1.45 (s, 12H), 1.37 (t, J=7.2Hz, 3H).

Step 5

To a solution of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (100 mg, 0.306 mmol) and3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidethyl ester (133 mg, 0.460 mmol) in toluene were added Pd(PPh₃)₄ (35.4mg, 0.0306 mmol) and K₃PO₄ (260 mg, 1.23 mmol). The resulting mixturewas bubbled with N₂ for 5 mins and stirred at 130° C. irradiated bymicrowave for 2 hrs. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford7-(2-ethoxycarbonyl-6-methyl-phenyl)-3-isopropyl-6-methyl-imidazo[1,2-b]pyrazole-1-carboxylicacid (21.2 mg, yield: 18%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.49 (d, J=7.2 Hz, 1H), 7.42-7.35 (m, 2H),7.29-7.22 (m, 1H), 3.90-3.80 (m, 1H), 3.79-3.69 (m, 2H), 2.31 (s, 3H),2.03 (s, 3H), 1.40 (t, J=7.2 Hz, 6H), 0.56 (t, J=7.2 Hz, 3H).

Step 6

To a solution of7-(2-ethoxycarbonyl-6-methyl-phenyl)-3-isopropyl-6-methyl-imidazo[1,2-b]pyrazole-1-carboxylicacid (21.2 mg, 0.056 mmol) in MeOH/H₂O (10 mL+5 mL) was added solid NaOH(22 mg, 0.56 mmol). The resulting mixture was stirred at 65° C.overnight. Then MeOH was removed in vacuum to give an aqueous residue,which was acidified to pH 3-4 with 1 M aqueous HCl. The yellow solidprecipitated from the mixture was collected by filtration. The cake waswashed with H₂O (20 mL×2) and air-dried to afford3-(2-carboxy-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (16.2 mg, yield: 83%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.72 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.2 Hz,1H), 7.45 (d, J=7.2 Hz, 1H), 7.34 (s, 1H), 3.90-3.80 (m, 1H), 2.24 (s,3H), 2.01 (s, 3H), 1.43 (d, J=6.8 Hz, 6H). MS: m/z 353.8 (M+H⁺).

Step 13-(2-Chloro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

To a solution of 2-bromo-1-chloro-3-methyl-benzene (500 mg, 2.43 mmol)and 4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (927mg, 3.65 mmol) in dioxane/H₂O (30 mL+10 mL) were added Pd(dppf)Cl₂ (178mg, 0.243 mmol) and KOAc (955 mg, 9.73 mmol). The resulting mixture wasdegassed and refilled with N₂ for 3 times and stirred at 90° C. under N₂atmosphere overnight. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=50/1) to afford2-(2-chloro-6-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(404 mg, yield: 66%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.18-7.09 (m, 2H), 7.01 (dd, J=7.2, 0.8 Hz,1H), 2.37 (s, 3H), 1.41 (s, 12H).

Step 2

To a solution of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (200 mg, 0.613 mmol) and2-(2-chloro-6-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(186 mg, 0.735 mmol) in toluene (8 mL) were added Pd(PPh₃)₄ (70.8 mg,0.0613 mmol) and K₃PO₄ (520 mg, 2.46 mmol). The resulting mixture wasbubbled with N₂ for 5 mins and stirred at 130° C. irradiated bymicrowave for 2 hrs. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford3-(2-chloro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (77.4 mg, yield: 34%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.38 (s, 1H), 7.37-7.33 (m, 1H), 7.25-7.22(m, 2H), 4.49-4.36 (m, 2H), 4.02-3.93 (m, 1H), 2.39 (s, 3H), 2.11 (s,3H), 1.51 (t, J=6.4 Hz, 6H), 1.40 (t, J=7.2 Hz, 3H). MS: m/z 371.8(M+H⁺).

3-(2-Chloro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 3

To a solution of3-(2-chloro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (38.2 mg, 0.103 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (17.2 mg, 0.411 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH 3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2) and combined organic layers wereconcentrated in vacuum to afford3-(2-chloro-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (32.6 mg, yield: 92%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.41 (dd, J=6.4, 2.8 Hz, 1H), 7.35-7.30 (m,2H), 7.22 (s, 1H), 3.80-3.71 (m, 1H), 2.23 (s, 3H), 2.02 (s, 3H), 1.40(d, J=6.8 Hz, 6H). MS: m/z 344.0 (M+H⁺).

3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

A mixture of 2-(2,6-difluorophenyl)acetonitrile (2.0 g, 13 mmol) and NaH(1.1 g, 26 mmol) in EtOAc (30 mL) was stirred at room temperature for 2hrs. The mixture was poured into ice-water (30 mL), adjusted to pH=7.The organic phase was separated. The aqueous phase was extracted withEtOAc (20 mL×3). The combined extracts were washed with brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated in vacuum. The residue waspurified by silica gel column (PE/EA=5/1) to give2-(2,6-difluorophenyl)-3-oxobutanenitrile (2.4 g, yield: 96%) as a whitesolid.

Step 2

A mixture of 2-(2,6-difluorophenyl)-3-oxobutanenitrile (2.4 g, 12 mmol),NH₂NH₂.H₂O (1.2 g, 25 mmol) and AcOH (2.3 g, 38 mmol) in EtOH (20 mL)was stirred at reflux for 2 hrs. The mixture was concentrated in vacuumand the residue was partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was separated. The aqueous phase was extracted withEtOAc (20 mL×3). The combined extracts were washed with brine (20 mL),dried over Na₂SO₄ and concentrated in vacuum. The residue was purifiedby silica gel column (PE/EA=1/1) to give4-(2,6-difluorophenyl)-3-methyl-1H-pyrazole (1.3 g, yield: 52%) as awhite solid.

Step 3

A mixture of 4-(2,6-difluorophenyl)-3-methyl-1H-pyrazole (325 mg, 1.6mmol) and ethyl 5-methyl-2,4-dioxohexanoate (320 mg, 1.7 mmol) in EtOH(5.0 mL) was stirred at reflux for 16 hrs. The mixture was concentratedin vacuum to remove most of EtOH and then filtered. The filer cake wasdried in vacuum to give ethyl3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(210 mg, yield: 36%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.62-7.54 (m, 1H), 7.44 (s, 1H), 7.31-7.27 (m,2H), 4.40-4.35 (m, 2H), 3.89-3.81 (m, 1H), 2.41 (s, 3H), 1.44 (d, J=8Hz, 6H), 1.33-1.30 (m, 3H). MS: m/z 360.1 (M+H⁺).

Step 4

A mixture of ethyl3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(185 mg, 0.52 mmol) and LiOH.H₂O (110 mg, 2.58 mmol) in THF/H₂O (3mL/2.0 mL) was stirred at room temperature for 2 hrs. The mixture wasconcentrated in vacuum and the residue was adjusted to pH=7 andextracted with EtOAc (10 mL×3). The combined extracts were washed withbrine (10 mL), dried over Na₂SO₄ and concentrated in vacuum to give3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (85 mg, yield: 49%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.61-7.54 (m, 1H), 7.44 (s, 1H), 7.30-7.26 (m,2H), 3.98-3.91 (m, 1H), 2.41 (s, 3H), 1.44 (d, J=8 Hz, 6H). MS: m/z332.1 (M+H⁺).

3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.60-7.52 (m, 2H), 7.44-7.39 (m, 2H),4.39-4.34 (q, J=8.0 Hz, 2H), 3.90-3.83 (m, 1H), 2.37 (s, 3H), 1.46-1.44(m, 6H), 1.33-1.29 (m, 3H). MS: m/z 376.1 (M+H⁺).

3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.59-7.52 (m, 2H), 7.43-7.38 (m, 2H),3.90-3.83 (m, 1H), 2.37 (s, 3H), 1.45-1.43 (m, 6H). MS: m/z 348.0 (M+H⁺)

3-(2-chloro-6-methoxyphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

A mixture of3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicacid (50 mg, 0.14 mmol) and MeONa (10 mg, 0.14 mmol) in MeOH (3 mL) wasstirred at 150° C. in microwave for 0.5 hour. The mixture was adjustedto pH=7 and extracted with EA (10 mL×3). The combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated in vacuum. Theresidue was purified by TLC to give3-(2-chloro-6-methoxyphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (4.9 mg, yield: 9.7%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.49 (m, 3H), 7.43 (m, 1H), 3.5 (m, 4H), 2.40(s, 3H), 1.51 (d, J=8.0 Hz, 6H). MS: m/z 361.8 (M+H⁺).

3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.55 (m, 2H), 7.52 (s, 1H), 7.47 (m, 1H), 4.42(q, J=8.0 Hz, 2H), 3.90-3.83 (m, 1H), 2.36 (s, 3H), 1.51 (d, J=8.0 Hz,6H), 1.37 (t, J=8.0 Hz, 3H). MS: m/z 392.0 (M+H⁺)

3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.67-7.65 (m, 2H), 7.55-7.51 (m, 1H), 7.42 (s,1H), 3.90-3.83 (m, 1H), 2.33 (s, 3H), 1.45-1.43 (m, 6H). MS: m/z 364.0(M+H⁺).

3-(2-Cyano-6-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a suspension of7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethylester (100 mg, 0.403 mmol), 2-bromo-3-fluoro-benzonitrile (121 mg, 0.605mmol), K₂CO₃ (111 mg, 0.806 mmol) and PPh₃ (52 mg, 20 mol %) in1.4-dioxane (5 mL) was added Pd(OAc)₂ (22 mg, 10 mol %). The vial wasbubbled with N₂ for a minute. The mixture was heated to 140° C. bymicrowave for 3 hrs. The solution was removed in vacuum. The residue waspurified by silica gel to give3-(2-cyano-6-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (20 mg, yield: 14%) as a yellow solid.

Step 2

To a solution of3-(2-cyano-6-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (20 mg, 0.0543 mmol) in THF/H₂O (8 mL/2 mL) was addedLiOH (7 mg, 0.16 mmol), and the reaction solution was stirred at roomtemperature overnight. The reaction mixture was evaporated to remove thesolvent. The residue was acidified with dilute HCl till pH=3-4. Theresulting solid was filtered to afford3-(2-cyano-6-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (10 mg, yield: 55%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.90 (d, J=8.0 Hz, 1H), 7.87-7.71 (m, 2H),7.43 (s, 1H), 3.96-3.92 (m, 1H), 2.42 (s, 3H), 1.44 (d, J=7.6 Hz, 6H).MS: m/z 339.0 (M+H⁺).

3-(2-Bromo-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.58-7.55 (m, 1H), 7.46 (s, 1H), 7.34 (d,J=7.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.41 (q, J=8.0 Hz, 2H), 5.00-3.93(m, 1H), 2.34 (s, 3H), 2.07 (s, 3H), 1.53-1.51 (m, 6H) 1.39 (t, J=7.2Hz, 3H). MS: m/z 416.0 (M+H⁺).

3-(2-Bromo-6-methyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-difluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.63-7.61 (m, 1H), 7.40-7.39 (m, 2H),7.32-7.28 (m, 1H), 3.87-3.84 (m, 1H), 2.30 (s, 3H), 2.02 (s, 3H),1.45-1.43 (m, 6H). MS: m/z 388.0 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a stirred solution of 3-methyl-butan-2-one (17.0 g, 0.20 mol) in THF(200 mL) cooled at −60˜−70° C. was added LiHMDS (220 mL, 0.22 mol). Themixture was stirred at −78° C. for 30 mins. Oxalic acid diethyl ester(34 g, 0.22 mol) was added at −78° C. The mixture was stirred for 16hrs. The mixture was concentrated in vacuum. The residue was adjusted topH=3-4 and extracted with EtOAc (80 mL×3). The combined extracts werewashed brine (50 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by column chorography on silica gel to give5-methyl-2,4-dioxo-hexanoic acid ethyl ester (28.8 g, yield: 77%) asorange oil.

¹HNMR (400 MHz, CDCl₃): δ=6.41 (s, 1H), 4.35 (q, J=7.2 Hz, 2H),2.67-2.66 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.19 (d, J=6.8 Hz, 6H). MS:m/z 187.1 (M+H⁺).

Step 2

A mixture of 5-methyl-1H-pyrazol-3-ylamine (500 mg, 5.15 mmol) and5-methyl-2,4-dioxo-hexanoic acid ethyl ester (1.05 g, 5.66 mmol) in EtOH(15 mL) was stirred at reflux overnight. The mixture was concentrated invacuum to give7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethylester (750 mg, 63%) as a yellow solid, which was used in next stepwithout further purification.

¹HNMR (400 MHz, DMSO-d6): δ=7.34 (s, 1H), 6.80 (s, 1H), 4.39 (q, J=7.2Hz, 2H), 3.85-3.75 (m, 1H), 2.50 (s, 3H), 1.37 (d, J=6.8 Hz, 6H), 1.26(t, J=7.2 Hz, 3H). MS: m/z 248.1 (M+H⁺).

Step 3

To a mixture of crude7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethylester (750 mg, 3.04 mmol) in CCl₄ (10 mL) was added NBS (540 mg, 3.04mmol). The mixture was stirred at room temperature overnight. Themixture was filtered. The solution was concentrated in vacuum and theresidue was purified by silica gel column (PE/EA=10/1) to give3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (755 mg, yield: 76%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.44 (s, 1H), 4.89 (q, J=7.2 Hz, 2H),3.91-3.80 (m, 1H), 2.52 (s, 3H), 1.47-1.43 (m, 9H). MS: m/z 326.2(M+H⁺).

Step 4

To a suspension of3-bromo-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (200 mg, 6.12 mmol) and (2,6-dimethylphenyl)boronic acid(128.4 mg, 8.56 mmol), K₃PO₄ (520 mg, 24.5 mmol) in toluene (5 mL) wasadded Pd(PPh₃)₄ (80 mg). The vial was bubbled with N₂ for a minute. Themixture was heated to 160° C. by microwave for 3 hrs. The solution wasremoved under reduced pressure. The residue was purified by silica gelcolumn to give3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (50 mg, yield: 23%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.44 (s, 1H), 7.22-7.15 (m, 3H), 4.43-4.37 (m,2H), 3.96-3.92 (m, 1H), 2.30 (s, 3H), 1.98 (s, 6H), 1.51 (d, J=6.4 Hz,6H), 1.37 (t, J=7.2 Hz, 3H). MS: m/z 352.0 (M+H⁺).

Step 5

To a solution of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (46 mg, 0.13 mmol) in THF/H₂O (10 mL) was added LiOH(16 mg, 0.39 mmol), and the reaction solution was stirred at roomtemperature overnight. The reaction mixture was evaporated to remove thesolvent. The residue was acidified with dilute HCl till pH=3-4. Theresulting solid was filtered to afford3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (10 mg, yield: 24%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.49 (s, 1H), 7.21-7.16 (m, 3H), 3.96-3.92 (m,1H), 2.30 (s, 3H), 2.02 (s, 6H), 1.53 (d, J=6.8 Hz, 6H). MS: m/z 324.0(M+H⁺).

7-Isopropyl-3-(4-methoxy-2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.42 (s, 1H), 6.74 (s, 2H), 4.42-4.38 (m, 2H),3.96-3.82 (m, 1H), 3.82 (s, 3H), 2.28 (s, 3H), 1.95 (s, 6H), 1.50 (d,J=6.8 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). MS: m/z 382.2 (M+H⁺)

3-(4-Fluoro-2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.44 (s, 1H), 6.92 (d, J=9.6 Hz, 2H),4.44-4.38 (m, 2H), 3.96-3.92 (m, 1H), 2.30 (s, 3H), 1.98 (s, 6H), 1.51(d, J=7.2 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H). MS: m/z 370.2 (M+H⁺).

7-Isopropyl-3-(4-methoxy-2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.47 (s, 1H), 6.72 (s, 2H), 3.90-3.82 (m, 1H),3.80 (s, 3H), 2.25 (s, 3H), 1.95 (s, 6H), 1.49 (d, J=7.2 Hz, 6H). MS:m/z 354.2 (M+H⁺)

3-(4-Fluoro-2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.48 (s, 1H), 6.91 (d, J=9.2 Hz, 2H),3.96-3.92 (m, 1H), 2.30 (s, 3H), 2.00 (s, 6H), 1.51 (d, J=6.8 Hz, 6H).MS: m/z 342.1 (M+H⁺).

3-(4-Chloro-2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.45 (s, 1H), 7.20 (s, 2H), 4.44-4.38 (m, 2H),3.96-3.86 (m, 1H), 2.30 (s, 3H), 1.98 (s, 6H), 1.50 (d, J=6.8 Hz, 6H),1.30 (t, J=8.0 Hz, 3H). MS: m/z 386.2 (M+H⁺).

3-(4-Chloro-2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.47 (s, 1H), 7.18 (s, 2H), 3.96-3.92 (m, 1H),2.30 (s, 3H), 1.97 (s, 6H), 1.28 (t, J=7.6 Hz, 6H). MS: m/z 358.1(M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

A suspension of 2,6-dimethyl-benzoic acid (33.0 g, 200.0 mmol), K₂CO₃(41.4 g, 300.0 mmol) and sulfuric acid dimethyl ester (28.0 g, 220.0mmol) in a solution of acetone (500 mL) was stirred at room temperatureovernight. TLC showed the reaction was completed. The solvent wasremoved in vacuum. Water (100 mL) was added. The mixture was extractedwith DCM (300 mL×3). The organic layer was washed with brine (500 mL),dried over Na₂SO₄ and concentrated to give 2,6-dimethyl-benzoic acidmethyl ester (33.0 g, yield: 100%) as a yellow oil.

Step 2

To a solution of 2,6-dimethyl-benzoic acid methyl ester (8.2 g, 50.00mmol) in THF (100 mL) was added LiAlH₄ (5.7 g, 150.0 mmol). The mixturewas stirred at 0° C. for 2 hrs. The reaction was quenched with water (6mL) followed by 20% aqueous NaOH (6 mL). The resulting solid wasfiltered and the filtrate was concentrated to give(2,6-dimethyl-phenyl)-methanol (5.7 g, yield: 84%) as a white solid.

¹HNMR (400 MHz, CDCl₃): δ=7.13-7.03 (m, 3H), 4.74 (s, 2H), 2.43 (s, 6H).

Step 3

To a solution of (2,6-dimethyl-phenyl)-methanol (13.6 g, 100.00 mmol) inDCM (400 mL) was added PBr₃ (5.7 g, 150.0 mmol) and pyridine (0.5 mL).The mixture was stirred at 0° C. for 2 hrs. TLC showed the reaction wascompleted. The reaction was quenched with slow addition of ice water (50mL). The aqueous phase was extracted with DCM (300 mL×3). The organiclayer was washed with brine (500 mL), dried over Na₂SO₄ and concentratedto give 2-bromomethyl-1,3-dimethyl-benzene (19.1 g, yield: 96%) as ayellow solid.

Step 4

A suspension of 2-bromomethyl-1,3-dimethyl-benzene (18.5 g, 92.50 mmol),KCN (9.0 g, 138.75 mmol) in a solution of DMF (100 mL) was stirred at50° C. overnight. TLC showed the reaction was completed. The solvent wasremoved in vacuum. Water (100 mL) was added. The mixture was extractedwith DCM (200 mL×3). The organic layer was washed with brine (500 mL),dried over Na₂SO₄ and concentrated to give(2,6-dimethyl-phenyl)-acetonitrile (13.5 g, yield: 81%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃): δ=7.16-6.99 (m, 3H), 3.63 (s, 2H), 2.39 (s,6H).

Step 5

To a solution of o-tolyl-acetonitrile (1.00 g, 7.6 mmol) and EtOAc (3.0mL, 30.5 mmol) in THF (15 mL) was added NaH (0.91 g, 22.9 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was adjusted to pH=6 with HCl (1 mol/L) and was extracted withEtOAc (10 mL×3). The combined organic layer was washed with brine andwas dried over Na₂SO₄. The solution was concentrated and purified bysilica gel column (PE/EtOAc=6/1) to afford 3-oxo-2-o-tolyl-butyronitrile(870 mg, yield: 70%) as a yellow oil.

Step 6

To a solution of 2-(2-fluoro-phenyl)-3-oxo-butyronitrile (1.50 g, 8.47mmol) in EtOH (20 mL) was added hydrazine monohydrochloride (1.28 g,18.64 mmol), and the mixture was stirred at 80° C. overnight. Then thereaction mixture was evaporated to remove the solvent. The residue wasdissolved in EtOAc (50 mL), and washed with saturated NaHCO₃ solution(20 mL), followed by brine (20 mL). The solution was dried over Na₂SO₄and concentrated to dryness in vacuum. The residue was purified bysilica gel column chromatography (DCM/MeOH=40/1) to afford4-(2-fluoro-phenyl)-5-methyl-1H-pyrazol-3-ylamine (1.20 g, yield: 75%)as a yellow solid.

Step 7

4-(2-Fluoro-phenyl)-5-methyl-1H-pyrazol-3-ylamine (300 mg, 1.56 mmol)and 2,4-dioxo-hexanoic acid ethyl ester (324 mg, 1.74 mmol) weredissolved in EtOH (10 mL), stirred at 80° C. overnight. The reactionmixture was evaporated and the residue was purified by silica gel columnchromatography (PE/EtOAc=20/1) to afford3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (350 mg, yield: 66%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ=8.45 (s, 1H), 7.45 (s, 1H), 7.25-7.17 (m,3H), 4.40-4.34 (m, 2H), 3.91-3.88 (m, 1H), 2.05 (s, 6H), 1.47-1.46 (m,6H), 1.33-1.29 (m, 3H). MS: m/z 337.9 (M+H⁺)

Step 8

To a solution of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (200 mg, 0.59 mmol) in THF/H₂O (10 mL) was added LiOH(74 mg, 1.76 mmol), stirred at rt for 3 h. The reaction mixture wasevaporated to remove the solvent. The residue was adjusted with diluteHCl till pH=3-4, filtrated, affording3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (128 mg, yield: 69%) as a yellow solid without purification.

¹H NMR (400 MHz, DMSO-d₆): δ=13.68 (brs, 1H), 8.42 (s, 1H), 7.44 (s,1H), 7.25-7.17 (m, 3H), 3.92-3.85 (m, 1H), 2.05 (s, 6H), 1.47-1.46 (m,6H). MS: m/z 310.0 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester Step 1

To a stirred solution of 3-methyl-butan-2-one (17 g, 0.20 mol) inanhydrous THF (200 mL) was added LiHMDS (220 mL, 0.22 mol) at −78° C.The resulting mixture was stirred at the same temperature for 30 minutesand then oxalic acid diethyl ester (34 g, 0.22 mol) was added. Themixture was stirred at room temperature for 16 hrs. The mixture wasconcentrated in vacuum. The residue was adjusted to pH=7.0 and extractedwith EtOAc (200 mL×3). The combined extracts were washed with brine,dried over Na₂SO₄ and concentrated in vacuum. The residue was purifiedby silica gel column chromatography (PE/EA=4/1) to give5-methyl-2,4-dioxo-hexanoic acid ethyl ester (28.8 g, yield: 77%) as ayellow liquid.

¹HNMR (400 MHz, CDCl₃): δ=6.41 (s, 1H), 4.35 (q, J=7.2 Hz, 2H),2.67-2.66 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.19 (d, J=6.8 Hz, 6H). MS:m/z 187.1 (M+H)⁺.

Step 2

A mixture of 5-isopropyl-1H-pyrazol-3-ylamine (450 mg, 3.60 mmol) and5-methyl-2,4-dioxo-hexanoic acid ethyl ester (742 mg, 4.05 mmol) in EtOH(5 mL) was stirred at reflux overnight. The mixture was concentrated invacuum to give 2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (1.01 g, 102%) as a yellow solid, which was used innext step without further purification.

Step 3

A mixture of crude2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethyl ester(990 mg, 3.60 mmol) and NBS (705 mg, 4.0 mmol) in CCl₄ (10 mL) wasstirred at reflux for 1 hour. The mixture was concentrated in vacuum andthe residue was purified by silica gel column (PE/EA=5/1) to give3-bromo-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (1.00 g, yield: 76%) as a yellow solid.

¹HNMR (400 MHz, DMSO): δ=7.41 (s, 1H), 4.51-4.40 (q, J=8.0 Hz, 2H),3.82-3.78 (m, 1H), 3.29-3.14 (m, 1H), 1.41-1.21 (m, 15H).

Step 4

A suspension of3-bromo-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (200 mg, 0.56 mmol), (2,6-dimethylphenyl)boronic acid (128mg, 0.84 mmol), K₃PO₄ (480 mg, 2.26 mmol) and Pd(PPh₃)₄ (80 mg, 0.056mmol) in anhydrous toluene (5.0 mL) was de-gassed and purged with N₂ forseveral times. The suspension was stirred at 130° C. for 0.5 hr and thesuspension was cooled to room temperature. Then the suspension wasstirred at 160° C. for 0.5 hr. The mixture was cooled to roomtemperature and filtered. The filtrate was concentrated in vacuum. Theresidue was purified by flash chromatography to give ethyl3-(2,6-dimethylphenyl)-2,7-diisopropylpyrazolo[1,5-a]pyrimidine-5-carboxylate(11 mg, yield: 4%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.41 (s, 1H), 7.23-7.20 (q, J=4.0 Hz, 1H),7.16-7.14 (m, 2H), 4.42-4.37 (q, J=8 Hz, 2H), 4.00-3.93 (m, 1H),2.92-2.85 (m, 1H), 1.98 (s, 6H), 1.53-1.51 (d, J=8.0 Hz, 6H), 1.39-1.35(t, J=8 Hz, 3H), 1.28-1.26 (d, J=8.0 Hz, 6H). MS: m/z 379.9 (M+H⁺).

Step 5

A mixture of ethyl3-(2,6-dimethylphenyl)-2,7-diisopropylpyrazolo[1,5-a]pyrimidine-5-carboxylate(35 mg, 0.09 mmol) and LiOH.H₂O (12 mg, 0.27 mmol) in THF/H₂O (3.0mL/2.0 mL) was stirred at room temperature for 2 hours. The mixture wasconcentrated in vacuum. The residue was adjusted to pH=3-4 and extractedwith EA (3 mL×3). The combined extracts were washed with brine, driedover Na₂SO₄ and concentrated in vacuum to give3-(2,6-dimethylphenyl)-2,7-diisopropylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (26 mg, yield: 83%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.45 (s, 1H), 7.23-7.19 (q, J=8.0 Hz, 1H),7.16-7.14 (m, 2H), 4.00-3.93 (m, 1H), 2.92-2.85 (m, 1H), 1.99 (s, 6H),1.53-1.51 (d, J=8.0 Hz, 6H), 1.28-1.26 (d, J=8.0 Hz, 6H). MS: m/z 352.1(M+H⁺)

2-Cyclopropyl-7-isopropyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.99 (d, J=8.0 Hz, 2H), 7.49 (t, J=8.0 Hz,2H), 7.38-7.38 (m, 2H), 4.49-4.44 (m, 2H), 3.96-3.80 (m, 1H), 2.35-2.25(m, 1H), 1.46-1.42 (m, 9H), 1.22-1.20 (m, 2H), 1.09-1.07 (m, 2H). MS:m/z 350.2 (M+H⁺).

2-Cyclopropyl-7-isopropyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.83 (d, J=8.0 Hz, 2H), 7.52-7.34 (m, 4H),3.96-3.80 (m, 1H), 2.35-2.25 (m, 1H), 1.49-1.47 (m, 6H), 1.20-1.07 (m,4H). MS: m/z 322.1 (M+H⁺)

2-Ethyl-7-isopropyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic Acid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.71-7.68 (m, 2H), 7.52-7.46 (m, 3H),7.37-7.34 (m, 1H), 3.96-3.80 (m, 1H), 3.10-3.02 (m, 2H), 1.50 (d, J=9.2Hz, 6H), 1.32 (m, 3H). MS: m/z 310.2 (M+H⁺)

3-(2,6-dimethylphenyl)-2-ethyl-7-isopropylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.46 (s, 1H), 7.22 (q, J=4.0 Hz, 1H),7.19-7.14 (m, 2H), 3.99-3.93 (m, 1H), 2.66 (q, J=7.6 Hz, 2H), 1.99 (s,6H), 1.53-1.51 (d, J=8.0 Hz, 6H), 1.20-1.17 (t, J=8.0 Hz, 3H). MS: m/z337.9 (M+H⁺)

3-(2,6-dimethylphenyl)-7-isopropyl-2-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.61-7.59 (m, 2H), 7.50 (s, 1H), 7.29-7.22 (m,4H), 7.16-7.14 (m, 2H), 4.40 (q, J=8.0 Hz, 2H), 4.11-4.01 (m, 1H), 1.93(s, 6H), 1.57 (d, J=8.0 Hz, 6H), 1.37 (t, J=8.0 Hz, 3H). MS: m/z 413.9(M+H⁺)

3-(2,6-dimethylphenyl)-7-isopropyl-2-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.61-7.59 (m, 3H), 7.31-7.25 (m, 4H),7.16-7.14 (m, 2H), 4.11-4.01 (m, 1H), 1.93 (s, 6H), 1.59-1.57 (d, J=8.0Hz, 6H). MS: m/z 385.9 (M+H⁺)

2-cyclobutyl-3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.45 (s, 1H), 7.22-7.18 (m, 1H), 7.16-7.14 (m,2H), 4.05-3.98 (m, 1H), 3.51-3.29 (m, 1H), 2.48-2.38 (m, 2H), 2.23-2.15(m, 2H), 2.00-1.91 (m, 8H), 1.55-1.53 (d, J=8.0 Hz, 6H). MS: m/z 364.1(M+H⁺).

2-cyclopropyl-3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.42 (s, 1H), 7.23-7.19 (m, 1H), 7.17-7.154(m, 2H), 3.91-3.85 (m, 1H), 2.05 (s, 6H), 1.74-1.68 (m, 1H), 1.49-1.47(d, J=8.0 Hz, 6H), 1.08-1.07 (m, 2H), 0.99-0.95 (m, 2H). MS: m/z 349.9(M+H⁺)

3-(2,6-Dimethyl-phenyl)-7-isopropyl-pyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid Dimethyl Ester

The title compound was prepared using general procedure of3-(2,6-Dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.63 (s, 1H), 7.22-7.19 (m, 1H), 7.13-7.11 (m,2H), 3.95 (m, 1H), 3.94 (s, 3H), 3.78 (s, 3H), 1.94 (s, 6H), 1.54-1.52(d, J=8.0 Hz, 6H). MS: m/z 382.1 (M+H⁺)

3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-2,5-dicarboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.65 (s, 1H), 7.18 (m, 1H), 7.12 (m, 2H), 4.06(m, 1H), 1.98-1.97 (s, 6H), 1.54-1.52 (d, J=8.0 Hz, 6H). MS: m/z 353.9(M+H⁺)

2-(dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-5-carboxylate

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.21-7.17 (m, 1H), 7.12-7.10 (m,2H), 4.44-4.39 (m, 2H), 3.98-3.91 (m, 1H), 3.03 (s, 3H), 3.02 (s, 3H),2.04 (s, 6H), 1.53 (d, J=8.0 Hz, 6H), 1.39-1.36 (m, 3H). MS: m/z 409.1(M+H⁺).

2-(dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-isopropylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2,7-diisopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.48 (s, 1H), 7.08-7.04 (m, 1H), 6.99-6.98 (m,2H), 3.98-3.91 (m, 1H), 2.94-2.91 (s, 6H), 1.95 (s, 6H), 1.43-1.41 (d,J=8.0 Hz, 6H). MS: m/z 381.1 (M+H⁺)

3-(2,6-Dimethyl-phenyl)-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester Step 1

To a solution of 5-nitro-2H-pyrazole-3-carboxylic acid (1.00 g, 6.37mmol) in MeOH (20 mL) was added conc. H₂SO₄ (2 mL), and the resultingmixture was stirred at 65° C. overnight. Then MeOH was removed in vacuumto give a yellow residue, which was purified by silica gel column withDCM as eluent to afford 5-nitro-2H-pyrazole-3-carboxylic acid methylester (1.04 g, yield: 95%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=11.63 (brs, 1H), 7.41 (s, 1H), 4.01 (s, 3H).

Step 2

To a solution of 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (200mg, 1.17 mmol) in dry THF (10 mL) was added LiBH₄ (2.34 mL, 2 M in THF)at 0° C., and the resulting mixture was allowed to warm to roomtemperature and stirred overnight. The reaction was monitored by TLC.Then the reaction was quenched with H₂O (10 mL), and the mixture wasextracted with EtOAc (20 mL×3). The combined organic layers wereconcentrated in vacuum to afford (5-nitro-1H-pyrazol-3-yl)-methanol (154mg, yield: 92%) as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ=13.89 (brs, 1H), 6.86 (d, J=1.6 Hz, 1H),5.57 (brs, 1H), 4.53 (s, 2H).

Step 3

To a solution of (5-nitro-1H-pyrazol-3-yl)-methanol (150 mg, 1.05 mmol)in MeOH (20 mL) was added Pd/C (30 mg, 20% wt). The resulting mixturewas degassed and refilled with H₂ for 3 times and stirred at roomtemperature under H₂ atmosphere overnight. The reaction was monitored byTLC. Then Pd/C was filtered off and the filtrate was concentrated invacuum to give (5-amino-1H-pyrazol-3-yl)-methanol (110 mg, yield: 93%)as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ=5.29 (s, 1H), 4.93 (brs, 1H), 4.27 (s, 2H).

Step 4

To a solution of (5-amino-1H-pyrazol-3-yl)-methanol (100 mg, 0.88 mmol)in EtOH (20 mL) was added 5-methyl-2,4-dioxo-hexanoic acid ethyl ester(181 mg, 0.96 mmol). The resulting mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. Then EtOH was removed invacuum to give a residue, which was purified by a silica gel column with(DCM/MeOH=20/1) to afford2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (172 mg, yield: 74%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.37 (s, 1H), 6.91 (s, 1H), 5.47 (brs, 1H),4.73 (s, 2H), 4.40 (q, J=6.8 Hz, 2H), 3.85-3.74 (m, 1H), 1.40 (d, J=6.8Hz, 6H), 1.36 (t, J=7.2 Hz, 3H).

Step 5

To a solution of2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (172 mg, 0.65 mmol) in CCl₄ (20 mL) was added NBS (128 mg,0.72 mmol). The resulting mixture was stirred at 80° C. for 2 hrs. Thereaction was monitored by TLC. Then CCl₄ was removed in vacuum to give aresidue, which was purified by a silica gel column with (DCM/MeOH=30/1)to afford3-bromo-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (182 mg, yield: 82%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.46 (s, 1H), 4.70 (s, 2H), 4.43 (q, J=6.8Hz, 2H), 3.85-3.80 (m, 1H), 1.41-1.36 (m, 9H). MS: m/z 340.0 (M+H⁺).

Step 6

To a solution of3-bromo-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (660 mg, 1.92 mmol) and (2,6-dimethylphenyl) boronicacid (434 mg, 2.89 mmol) in toluene (2 mL) were added Pd(dppf)Cl₂ (141mg, 0.193 mmol) and K₃PO₄ (1.64 g, 7.72 mmol). The resulting mixture wasbubbled with N₂ for 5 mins and stirred at 130° C. irradiated bymicrowave for 2 hrs. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford3-(2,6-dimethyl-phenyl)-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (43 mg, yield: 6.1%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.43 (s, 1H), 7.23 (dd, J=8.4, 6.8 Hz, 1H),7.17-7.13 (m, 2H), 4.71 (d, J=6.8 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H),4.04-3.94 (m, 1H), 2.24 (brs, 1H), 2.04 (s, 6H), 1.52 (d, J=7.2 Hz, 6H),1.40 (t, J=7.2 Hz, 3H). MS: m/z 368.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 7

To a solution of3-(2,6-dimethyl-phenyl)-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (32.2 mg, 0.088 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (15 mg, 0.35 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH 3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2) and the combined organic layers wereconcentrated in vacuum to afford3-(2,6-dimethyl-phenyl)-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (13.2 mg, yield: 44%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.59 (s, 1H), 7.32-7.23 (m, 1H), 7.17-7.13(m, 2H), 4.73 (s, 2H), 4.10-3.97 (m, 1H), 2.21 (brs, 1H), 2.01 (s, 6H),1.53 (d, J=7.2 Hz, 6H). MS: m/z 340.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester Step 1

To a solution of3-bromo-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (200 mg, 0.58 mmol) in THF (10 mL) was added NaH (70mg, 1.75 mmol, 60%) at −5° C. After stirring at 0° C. for 0.5 hr, Mel(83.0 mg, 0.58 mmol) was added into the mixture. The resulting mixturewas stirred from 0° C. to room temperature for 2 hrs. The reaction wasmonitored by TLC. Then ice-water (10 mL) was added to quench thereaction, and the mixture was concentrated in vacuum to give a crudeproduct3-bromo-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid, which was used for next step without further purification. MS: m/z328.0 (M+H⁺).

Step 2

To a solution of3-bromo-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (crude) in MeOH (20 mL) was added conc. H₂SO₄ (2 mL). The resultingmixture was stirred at 65° C. overnight. The reaction mixture wasconcentrated in vacuum to give a residue, which was diluted with H₂O (10mL). The mixture was extracted with DCM (10 mL×2). The combined organiclayers were concentrated to give a crude product, which was purified bya silica gel column (DCM) to afford3-bromo-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (80 mg) as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ=7.49 (s, 1H), 4.75 (s, 2H), 4.05 (s, 3H),4.04-3.93 (m, 1H), 3.50 (s, 3H), 1.46 (d, J=6.9 Hz, 6H).

Step 3

To a solution of3-bromo-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (80 mg, 0.234 mmol) and (2,6-dimethylphenyl) boronicacid (52.6 mg, 0.351 mmol) in toluene were added Pd(dppf)Cl₂ (17 mg,0.0234 mmol) and K₃PO₄ (198 mg, 0.936 mmol). The resulting mixture wasbubbled with N₂ for 5 mins and stirred at 130° C. irradiated bymicrowave for 2 hrs. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (10.8 mg, yield: 12.6%) as a yellow solid.

¹HNMR (400 MHz, CDCl₃): δ=7.45 (s, 1H), 7.22 (dd, J=8.0, 6.8 Hz, 1H),7.17-7.12 (m, 2H), 4.47 (s, 2H), 4.14-4.12 (m, 1H), 3.94 (s, 3H), 3.36(s, 3H), 2.03 (s, 6H), 1.51 (d, J=6.8 Hz, 6H). MS: m/z 367.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 4

To a solution of3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (46 mg, 0.125 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (21 mg, 0.500 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH 3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (20 mL) and organic phase was concentrated invacuum to afford3-(2,6-dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (42 mg, yield: 95%) as a yellow solid.

¹H NMR (400 MHz, CD₃OD): δ=7.46 (s, 1H), 7.16 (dd, J=8.8, 6.4 Hz, 1H),7.02-7.06 (m, 2H), 4.43 (s, 2H), 3.99-3.86 (m, 1H), 3.31 (s, 3H), 1.99(s, 6H), 1.51 (d, J=7.2 Hz, 6H). MS: m/z 353.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-isopropyl-2-methoxymethyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a solution of3-bromo-2-hydroxymethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (100 mg, 0.292 mmol) in dry DCM (20 mL) was added MnO₂(127 mg, 1.46 mmol). The suspension mixture was stirred at roomtemperature overnight. The reaction was monitored by LCMS. Then MnO₂ wasfiltered off, and the filtrate was concentrated in vacuum to give3-bromo-2-formyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (96 mg, yield: 96%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=10.29 (s, 1H), 7.62 (s, 1H), 4.54 (q, J=6.8Hz, 2H), 4.04-3.92 (m, 1H), 1.56-1.44 (m, 9H).

Step 2

To a solution of3-bromo-2-formyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic acidethyl ester (994 mg, 2.93 mmol) and dimethyl-amine (HCl salt, 477 mg,5.86 mmol) in MeOH/H₂O (30 mL+5 mL) were added NaBH₃CN (185 mg, 2.93mmol) and NaBH(OAc)₃ (620 mg, 2.93 mmol). The resulting mixture wasstirred at room temperature overnight. Then the reaction mixture wasconcentrated in vacuum to give a residue, which was washed with H₂O (20mL) and extracted with EtOAc (20 mL×2). The combined organic layers wereconcentrated to give a crude product, which was purified by a silica gelcolumn (DCM/MeOH=50/1) to afford3-bromo-2-dimethylaminomethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (591 mg, yield: 55%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.51 (d, J=0.4 Hz, 1H), 4.53 (q, J=6.8 Hz,2H), 4.06 (s, 2H), 4.00-3.92 (m, 1H), 2.58 (s, 6H), 1.53-1.44 (m, 9H).

Step 3

To a solution of3-bromo-2-dimethylaminomethyl-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (210 mg, 0.568 mmol) and (2,6-dimethylphenyl) boronicacid (128 mg, 0.853 mmol) in toluene (3 mL) were added Pd(PPh₃)₄ (128mg, 0.0568 mmol) and K₃PO₄ (482 mg, 2.275 mmol). The resulting mixturewas bubbled with N₂ for 5 mins and stirred at 130° C. irradiated bymicrowave for 2 hrs. Then the reaction mixture was filtered, and thefiltrate was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford2-dimethylaminomethyl-3-(2,6-dimethyl-phenyl)-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (26.8 mg, yield: 12.6%) as a yellow solid.

Step 4

To a solution of2-dimethylaminomethyl-3-(2,6-dimethyl-phenyl)-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (26.8 mg, 0.068 mmol) in THF/H₂O (16 mL+4 mL) was addedLiOH (11.4 mg, 0.272 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH 3-4 with 1 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2) and organic phase was concentrated invacuum to afford2-dimethylaminomethyl-3-(2,6-dimethyl-phenyl)-7-isopropyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (18.6 mg, yield: 75%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=7.52 (s, 1H), 7.20 (dd, J=8.4, 6.4 Hz, 1H),7.16-7.10 (m, 2H), 3.96-3.87 (m, 1H), 3.80 (s, 2H), 2.47 (s, 6H), 1.99(s, 6H), 1.48 (d, J=6.4 Hz, 6H). MS: m/z 367.1 (M+H⁺).

7-Isopropyl-2,6-dimethyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹H NMR (400 MHz, DMSO-d₆): δ=7.66 (d, J=7.2 Hz, 2H), 7.48 (t, J=7.6 Hz,2H), 7.32 (t, J=7.2 Hz, 1H), 4.00 (m, 1H), 3.92 (s, 3H), 2.62 (s, 3H),2.37 (s, 3H), 1.55 (d, J=7.2 Hz, 6H). MS: m/z 324.1 (M+H)⁺.

7-Isopropyl-2,6-dimethyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹H NMR (300 MHz, CD₃OD): δ=7.73 (d, J=7.2 Hz, 2H), 7.47 (t, J=7.6 Hz,2H), 7.32 (t, J=7.2 Hz, 1H), 4.14 (m, 1H), 2.63 (s, 3H), 2.50 (s, 3H),1.66 (d, J=6.8 Hz, 6H). MS: m/z 308.1 (M−H⁻).

7-Ethyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic AcidEthyl Ester

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹H NMR (400 MHz, DMSO-d₆): δ=7.74 (d, J=7.6 Hz, 2H), 7.52 (d, J=7.6 Hz,1H), 7.49-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H),3.22 (q, J=7.2 Hz, 2H), 2.62 (s, 3H), 1.40 (d, J=7.5 Hz, 3H), 1.35 (t,J=7.2 Hz, 3H). MS: m/z 310.1 (M+H)⁺.

7-Ethyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic Acid

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹H NMR (300 MHz, CD₃OD): δ=7.65 (d, J=8.0 Hz, 2H), 7.38 (d, J=7.2 Hz,3H), 7.23 (t, J=7.2 Hz, 1H), 3.17 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 1.40(d, J=7.6 Hz, 3H). MS: m/z 280.1 (M−H⁻).

2-Methyl-3-phenyl-7-propyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic AcidEthyl Ester

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹H NMR (400 MHz, DMSO-d₆): δ=7.73 (d, J=7.6 Hz, 2H), 7.51 (d, J=7.6 Hz,2H), 7.45 (s, 1H), 7.35 (t, J=7.0 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H), 3.18(t, J=7.4 Hz, 2H), 2.61 (s, 3H), 1.87 (q, J=7.4 Hz, 2H), 1.35 (t, J=7.2Hz, 3H), 1.01 (t, J=7.2 Hz, 3H). MS: m/z 324.1 (M+H)⁺.

2-Methyl-3-phenyl-7-propyl-pyrazolo[1,5-a]pyrimidine-5-carboxylic Acid

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

H NMR (400 MHz, CD₃OD): δ=7.78 (d, J=7.6 Hz, 2H), 7.51 (t, J=7.4 Hz,3H), 7.36 (t, J=7.4 Hz, 1H), 3.25 (t, J=7.2 Hz, 2H), 2.68 (s, 3H), 1.98(q, J=7.2 Hz, 2H), 1.14 (t, J=7.4 Hz, 3H). MS: m/z 294.1 (M−H⁻).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester Step 1

To a stirred solution of 1-phenyl-ethanone (1.0 g, 8.33 mmol) in toluene(20 mL) was added NaH (433 mg, 10.8 mol). The mixture was stirred atroom temperature for 30 mins. Oxalic acid diethyl ester (1.7 mL, 12.5mmol) was added dropwise and stirred at room temperature overnight. Themixture was concentrated in vacuum. The residue was adjusted to pH=3-4and extracted with EtOAc (80 mL×3). The combined extracts were washedbrine, dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel column chorography to give 2,4-dioxo-4-phenyl-butyric acidethyl ester (1.2 g, yield: 66%) as brown oil.

Step 2

To a solution of 4-(2,6-dimethyl-phenyl)-5-methyl-1H-pyrazol-3-ylamine(200 mg, 0.995 mmol) and 2,4-dioxo-4-phenyl-butyric acid ethyl ester(278 mg, 1.035 mmol) in EtOH (10 mL) was stirred at 80° C. overnight.The reaction mixture was evaporated to dryness in vacuum. The residuewas purified by silica gel column chromatography (PE/EtOAc=20/1) toafford3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (60 mg, yield: 16.0%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=8.19-8.16 (m, 2H), 7.65-7.63 (m, 4H),7.22-7.16 (m, 3H), 4.45-4.39 (m, 2H), 2.27 (s, 3H), 2.02 (s, 6H), 1.38(t, J=8.8 Hz, 3H). MS: m/z 386.1 (M+H⁺)

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-isopropyl-2-methyl-3-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid amide.

¹HNMR (400 MHz, DMSO-d₆): δ=8.22-8.20 (m, 2H), 7.68-7.64 (m, 3H), 7.60(s, 1H), 7.28-7.19 (m, 3H), 2.24 (s, 3H), 1.99 (s, 6H). MS: m/z 357.8(M+H⁺)

7-Cyclobutyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.48 (s, 1H), 7.22-7.14 (m, 3H), 4.43-4.37 (m,2H), 4.36-4.32 (m, 1H), 2.68-2.60 (m, 2H), 2.50-2.38 (m, 2H), 2.26 (s,3H), 2.15-2.00 (m, 2H), 1.97 (s, 6H), 1.37 (t, J=7.2 Hz, 3H). MS: m/z364.2 (M+H⁺).

7-Cyclobutyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.50 (s, 1H), 7.19-7.12 (m, 3H), 4.38-4.32 (m,1H), 2.68-2.60 (m, 2H), 2.50-2.38 (m, 2H), 2.25 (s, 3H), 2.10-1.98 (m,2H), 1.97 (s, 6H). MS: m/z 336.2 (M+H⁺).

7-Cyclopentyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.37 (s, 1H), 7.22-7.14 (m, 3H), 3.96-3.88(m, 1H), 2.48-2.37 (m, 2H), 2.28 (s, 3H), 1.94 (s, 6H), 1.90-1.78 (m,6H). MS: m/z 350.2 (M+H⁺)

7-Cyclopentyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.45 (s, 1H), 7.22-7.14 (m, 3H), 4.43-4.37 (m,2H), 4.06-3.98 (m, 1H), 2.48-2.37 (m, 2H), 2.28 (s, 3H), 1.97 (s, 6H),2.00-1.87 (m, 6H), 1.36 (t, J=7.2 Hz, 3H). MS: m/z 378.5 (M+H⁺)

7-Cyclopropyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.21-7.14 (m, 4H), 2.98-2.86 (m, 1H), 2.29 (s,3H), 1.98 (s, 6H), 1.44-1.40 (m, 2H), 1.23-1.20 (m, 2H). MS: m/z 322.1(M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-ethyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.48 (s, 1H), 7.18-7.15 (m, 3H), 3.30-3.28 (m,2H), 2.28 (s, 3H), 1.98 (s, 6H), 1.50 (t, J=9.6 Hz, 3H). MS: m/z 310.1(M+H⁺).

7-Cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

3-(2,6-dimethyl-phenyl)-7-hydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester was prepared with the same procedure as3-(2,6-dimethyl-phenyl)-7-hydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester, which is shown in3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester. MS: m/z 312.1 (M+H⁺).

Step 2

A mixture of3-(2,6-dimethyl-phenyl)-7-hydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (3.25 g, 10 mmol) in POCl₃ (20 mL) was heated to 110°C. with stirring for 6 hrs. Then POCl₃ was removed in vacuum to give aresidue, which was purified by a silica gel column (DCM) to afford7-chloro-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (3.24 g, yield: 94%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=7.68 (s, 1H), 7.27-7.20 (m, 1H), 7.15 (d,J=7.6 Hz, 1H), 3.95 (s, 3H), 2.38 (s, 3H), 2.02 (s, 6H). MS: m/z 330.0(M+H⁺).

Step 3

To a solution of7-chloro-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid methyl ester (343 mg, 1.0 mmol) and cyclohex-1-enyl boronic acid(189 mg, 1.5 mmol) in dioxane/H₂O (30 mL+10 mL) were added Pd(dppf)Cl₂(732 mg, 0.1 mmol) and K₂CO₃ (552 mg, 4.0 mmol). The resulting mixturewas degassed and refilled with N₂ for 3 times and stirred at 90° C.overnight. Then the reaction mixture was concentrated in vacuum to givean aqueous residue, which was extracted with EtOAc (20 mL×3). Thecombined organic layers were concentrated to give a crude product, whichwas purified by a reversed-phase column (B from 5-95, A: H₂O, B: ACN) toafford7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (242 mg, yield: 67%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=7.22 (s, 1H), 7.20 (dd, J=8.8, 6.0 Hz, 1H),7.17-7.12 (m, 3H), 2.66-2.58 (m, 2H), 2.37-2.29 (m, 2H), 2.16 (s, 3H),1.94 (s, 6H), 1.83-1.75 (m, 2H), 1.74-1.66 (m, 2H). MS: m/z 361.9(M+H⁺).

To a solution of7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (64 mg, 0.177 mmol) in MeOH (10 mL) was added Pd/C (12.8 mg, 20%wt). The resulting mixture was degassed and refilled with H₂ for 3 timesand stirred at room temperature under H₂ atmosphere (balloon) for 3 hrs.Then Pd/C was filtered off and filtrate was concentrated in vacuum toafford7-cyclohexyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (22.8 mg, yield: 36%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=7.19 (dd, J=8.8, 6.0 Hz, 1H), 7.16-7.12 (m,3H), 3.55-3.45 (m, 1H), 2.17 (s, 3H), 2.15-2.09 (m, 2H), 2.03-1.98 (m,1H), 1.94 (s, 6H), 1.90-1.83 (m, 2H), 1.82-1.74 (m, 1H), 1.54-1.45 (m,4H). MS: m/z 363.9 (M+H⁺).

7-Cyclopent-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=8.10 (brs, 1H), 7.35 (s, 1H), 7.23 (dd,J=8.8, 6.4 Hz, 1H), 7.20-7.15 (m, 2H), 2.98-2.90 (m, 2H), 2.80-2.72 (m,2H), 2.25 (s, 3H), 2.08-2.00 (s, 2H), 1.94 (s, 6H). MS: m/z 347.9(M+H⁺).

3-(2,6-dimethyl-phenyl)-2-methyl-7-pyridin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=8.92 (dd, J=4.4, 1.2 Hz, 2H), 8.24 (dd,J=4.4, 1.6 Hz, 2H), 7.75 (s, 1H), 7.30 (dd, J=8.8, 6.4 Hz, 1H),7.27-7.22 (m, 2H), 2.29 (s, 3H), 2.04 (s, 6H). MS: m/z 358.8 (M+H⁺).

3-(2,6-dimethyl-phenyl)-7-furan-3-yl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=9.29 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H),7.55 (s, 1H), 7.25 (dd, J=8.8, 6.4 Hz, 1H), 7.21-7.16 (m, 2H), 2.31 (s,3H), 1.97 (s, 6H). MS: m/z 347.8 (M+H⁺).

3-(2,6-dimethylphenyl)-2-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of7-cyclohex-1-enyl-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.58 (s, 1H), 7.33 (s, 1H), 7.25-7.20 (m, 1H),7.19-7.15 (m, 2H), 4.05-4.02 (m, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.32-3.28(m, 2H), 2.29 (s, 3H), 1.99 (s, 6H). MS: m/z 363.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester Step 1

To a solution of t-BuOK (5.4 g, 48.12 mmol) in THF (40 mL) was addedToMIC (4.7 g, 24.06 mmol). The mixture was stirred at −78° C. for 0.5hr. Then 2,6-dimethyl-benzaldehyde (2.0 g, 15.0 mmol) was added and theresulting mixture was stirred at −78° C. for 1.5 hrs. Then MeOH (6 mL)was added into the reaction mixture. The mixture was allowed to warm toroom temperature and reflux for 2 hrs. Then the mixture was concentratedin vacuum to give a residue, which was mixed with water (50 mL) andextracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to give a crude product, which was purified by a silica gelcolumn (PE/EA=10/1) to afford (2,6-dimethyl-phenyl)-acetonitrile (1.7 g,yield: 79%) as a yellow oil.

¹HNMR (400 MHz, DMSO-d6): δ=7.13 (dd, J=8.8, 5.6 Hz, 1H), 7.11-7.06 (m,2H), 3.88 (s, 2H), 2.34 (s, 6H).

Step 2

To a solution of (2,6-dimethyl-phenyl)-acetonitrile (1.7 g, 11.7 mmol)and EA (4.6 mL, 46.9 mmol) in dry THF (25 mL) was added NaH (1.4 g, 35.1mmol). The resulting mixture was stirred at room temperature overnight.Then ice-water (50 mL) was added into the reaction mixture slowly. Themixture was acidified to pH=5-6 with 1 M aqueous HCl and extracted withEA (20 mL×3). The combined organic layers were concentrated in vacuum togive a crude product, which was purified by a silica gel column(PE/EA=6/1) to afford 2-(2,6-dimethyl-phenyl)-3-oxo-butyronitrile (2.10g, yield: 96%) as an orange oil.

¹HNMR (400 MHz, DMSO-d6): δ=7.12 (dd, J=8.8, 6.4 Hz, 1H), 7.09-7.02 (m,2H), 2.27 (s, 3H), 2.19 (s, 6H).

Step 3

To a solution of 2-(2,6-dimethyl-phenyl)-3-oxo-butyronitrile (2.10 g,11.2 mmol) in EtOH (40 mL) was added N₂H₄H₂O (1.12 g, 22.4 mmol) andAcOH (2.02 g, 33.6 mmol). The resulting mixture was stirred at 80° C.overnight. Then the reaction mixture was concentrated in vacuum to givea residue, which was mixed with H₂O (20 mL) and extracted with EtOAc (20mL×3). The combined organic layers were concentrated to give a crudeproduct 4-(2,6-dimethyl-phenyl)-5-methyl-2H-pyrazol-3-ylamine (2.08 g,yield: 92%) as a yellow oil, which was used for next step withoutfurther purification.

Step 4

To a solution of 4-(2,6-dimethyl-phenyl)-5-methyl-2H-pyrazol-3-ylamine(1.0 g, 5.0 mmol) in AcOH (5 mL) was added but-2-ynedioic acid diethylester (850 mg, 5.0 mmol). The resulting mixture was stirred at 80°overnight. Then the reaction mixture was allowed to cool to roomtemperature and H₂O (20 mL) was added. The yellow solid precipitatedfrom the mixture was collected by filtration. The cake was washed withH₂O (50 mL) and air-dried to afford3-(2,6-dimethyl-phenyl)-7-hydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (1.16 g, yield: 72%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=12.62 (brs, 1H), 7.23 (dd, J=8.0, 6.4 Hz,1H), 7.17-7.12 (m, 2H), 6.26 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.00 (s,3H), 1.97 (s, 6H), 1.31 (t, J=6.8 Hz, 3H).

Step 5

A mixture of3-(2,6-dimethyl-phenyl)-7-hydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (2.0 g, 6.15 mmol) in POCl₃ (20 mL) was heated to 110°C. with stirring overnight. Then POCl₃ was removed in vacuum to give aresidue, which was purified by a silica gel column (DCM) to afford7-chloro-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (1.98 g, yield: 94%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=7.65 (s, 1H), 7.24 (dd, J=8.0, 6.4 Hz, 1H),7.19-7.13 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 2.02 (s, 6H),1.40 (t, J=6.8 Hz, 3H).

Step 6

To a solution of7-chloro-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (56 mg, 0.163 mmol) in DMF (6 mL) was added phenylamine(30.3 mg, 0.326 mmol). The resulting mixture was stirred in sealed tubeat 100° C. overnight. Then DMF was removed in vacuum to give a residue,which was purified by prep-TLC (PE/EA=5/1) to afford3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (56.4 mg, yield: 86%) as a yellow solid.

¹HNMR (400 MHz, CDCl₃): δ=8.19 (brs, 1H), 7.50 (t, J=7.6 Hz, 2H), 7.44(d, J=7.6 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 7.21 (dd, J=8.0, 6.8 Hz, 1H),7.18-7.12 (m, 2H), 7.08 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 2.31 (s, 3H),2.08 (s, 6H), 1.35 (t, J=7.2 Hz, 3H). MS: m/z 401.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

To a solution of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (60.8 mg, 0.152 mmol) in THF/H₂O (20 mL+5 mL) was addedLiOH (19.2 mg, 0.456 mmol). The resulting mixture was stirred at roomtemperature overnight. Then THF was removed in vacuum to give an aqueousresidue, which was acidified to pH=2-3 with 2 M aqueous HCl. The mixturewas extracted with DCM (10 mL×2), and the combined organic layers wereconcentrated to afford3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (52.6 mg, yield: 93%) as a yellow solid.

¹HNMR (400 MHz, DMSO-d6): δ=10.21 (brs, 1H), 7.51 (d, J=4.4 Hz, 4H),7.36-7.29 (m, 1H), 7.23 (dd, J=8.8, 6.0 Hz, 1H), 7.20-7.15 (m, 2H), 6.78(s, 1H), 2.25 (s, 3H), 2.00 (s, 6H). MS: m/z 372.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-p-tolylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.11 (brs, 1H), 7.34-7.28 (m, 4H), 7.20 (dd,J=8.4, 6.0 Hz, 1H), 7.16-7.12 (m, 2H), 7.01 (s, 1H), 3.88 (s, 3H), 2.42(s, 3H), 2.31 (s, 3H), 2.07 (s, 6H). MS: m/z 400.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-p-tolylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=9.99 (brs, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.30(d, J=8.0 Hz, 2H), 7.22 (dd, J=8.8, 5.6 Hz, 1H), 7.19-7.14 (m, 2H), 6.69(s, 1H), 2.36 (s, 3H), 2.23 (s, 3H), 1.99 (s, 6H). MS: m/z 387.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-(4-fluoro-phenylamino)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.09 (brs, 1H), 7.45-7.38 (m, 2H), 7.24-7.18(m, 3H), 7.16-7.12 (m, 2H), 6.92 (s, 1H), 3.88 (s, 3H), 2.31 (s, 3H),2.07 (s, 6H). MS: m/z 405.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-(4-fluoro-phenylamino)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=9.76 (brs, 1H), 7.57-7.45 (m, 2H), 7.32 (t,J=8.8 Hz, 2H), 7.24-7.13 (m, 3H), 6.67 (s, 1H), 2.21 (s, 3H), 1.99 (s,6H). MS: m/z 390.8 (M+H⁺).

7-(4-Chloro-phenylamino)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.15 (brs, 1H), 7.48 (dd, J=6.8, 2.0 Hz, 2H),7.38 (dd, J=8.8, 2.0 Hz, 2H), 7.21 (dd, J=8.4, 2.4 Hz, 1H), 7.17-7.12(m, 2H), 7.03 (s, 1H), 3.89 (s, 3H), 2.31 (s, 3H), 2.06 (s, 6H). MS: m/z421.1 (M+H⁺).

7-(4-Chloro-phenylamino)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=10.10 (brs, 1H), 7.58-7.50 (m, 4H),7.25-7.21 (m, 3H), 6.81 (s, 1H), 2.24 (s, 3H), 1.99 (s, 6H). MS: m/z407.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-(4-methoxy-phenylamino)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.02 (brs, 1H), 7.35 (dd, J=6.8, 2.0 Hz, 2H),7.21 (dd, J=8.8, 6.4 Hz, 1H), 7.16-7.12 (m, 2H), 7.02 (dd, J=6.8, 2.0Hz, 2H), 6.87 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H) 2.31 (s, 3H), 2.08 (s,6H). MS: m/z 417.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-(4-methoxy-phenylamino)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=10.02 (brs, 1H), 7.41 (d, J=8.8 Hz, 2H),7.22 (dd, J=8.8, 6.0 Hz, 1H), 7.20-7.14 (m, 2H), 7.10-7.04 (m, 2H), 6.60(s, 1H), 3.82 (s, 3H), 2.24 (s, 3H), 1.99 (s, 6H). MS: m/z 403.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-trifluoromethyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.34 (brs, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.56(d, J=8.4 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 7.17-7.13 (m, 2H), 3.91 (s,3H), 2.32 (s, 3H), 2.07 (s, 6H). MS: m/z 417.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-trifluoromethyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=10.57 (brs, 1H), 7.87 (d, J=8.8 Hz, 2H),7.76 (d, J=8.4 Hz, 2H), 7.24 (dd, J=8.8, 6.0 Hz, 1H), 7.21-7.16 (m, 2H),6.97 (s, 1H), 2.27 (s, 3H), 1.99 (s, 6H). MS: m/z 440.8 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-trifluoromethoxy-phenylamino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.19 (brs, 1H), 7.50-7.45 (m, 2H), 7.36 (d,J=8.4 Hz, 2H), 7.21 (dd, J=8.4, 6.4 Hz, 1H), 7.18-7.12 (m, 2H), 7.05 (s,1H), 3.90 (s, 3H), 2.31 (s, 3H), 2.07 (s, 6H). MS: m/z 471.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-trifluoromethoxy-phenylamino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=10.40 (brs, 1H), 7.65 (dd, J=6.8, 2.0 Hz,2H), 7.76 (d, J=8.4 Hz, 2H), 7.24 (dd, J=8.4, 6.0 Hz, 1H), 7.20-7.16 (m,2H), 6.79 (s, 1H), 2.26 (s, 3H), 1.99 (s, 6H). MS: m/z 457.1 (M+H⁺).

7-(4-Cyano-phenylamino)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=8.43 (brs, 1H), 7.79 (dd, J=6.8, 2.0 Hz, 2H),7.54 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 7.21 (dd, J=8.4, 6.4 Hz, 1H),7.16-7.12 (m, 2H), 3.92 (s, 3H), 2.31 (s, 3H), 2.05 (s, 6H). MS: m/z412.1 (M+H⁺).

7-(4-Cyano-phenylamino)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=10.65 (brs, 1H), 7.95 (dd, J=6.8, 2.0 Hz,2H), 7.74 (d, J=8.8 Hz, 2H), 7.24 (dd, J=8.4, 6.0 Hz, 1H), 7.20-7.16 (m,2H), 7.03 (s, 1H), 2.27 (s, 3H), 1.99 (s, 6H). MS: m/z 397.8 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-phenyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.41 (t, J=8.0 Hz, 2H), 7.29-7.26 (m, 1H),7.25-7.11 (m, 3H), 715-7.11 (m, 2H), 6.82 (s, 1H), 3.88 (s, 3H), 3.86(s, 3H), 2.22 (s, 3H), 2.05 (s, 6H). MS: m/z 401.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-phenyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.46 (t, J=8.0 Hz, 2H), 7.35-7.26 (m, 3H),7.22 (dd, J=8.8, 6.0 Hz, 1H), 7.19-7.14 (m, 2H), 6.65 (s, 1H), 3.84 (s,3H), 2.12 (s, 3H), 1.96 (s, 6H). MS: m/z 386.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-p-tolyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.24-7.20 (m, 2H), 7.20-7.16 (m, 1H),7.16-7.11 (m, 4H), 6.72 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.40 (s,3H), 2.23 (s, 3H), 2.05 (s, 6H). MS: m/z 415.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-p-tolyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.32-7.21 (m, 5H), 7.20-7.15 (m, 2H), 6.65(s, 1H), 3.87 (s, 3H), 2.37 (s, 3H), 2.14 (s, 3H), 1.97 (s, 6H). MS: m/z400.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-[(4-fluoro-phenyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.23-7.16 (m, 3H), 7.15-7.08 (m, 4H), 76.76(s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.20 (s, 3H), 2.04 (s, 6H). MS: m/z419.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-[(4-fluoro-phenyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.42-7.35 (m, 2H), 7.32-7.25 (m, 2H), 7.22(dd, J=8.8, 6.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.62 (s, 1H), 3.81 (s, 3H),2.09 (s, 3H), 1.95 (s, 6H). MS: m/z 404.8 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CD₃OD): δ=7.20-7.14 (m, 3H), 6.91 (s, 1H), 4.38-4.36 (m,2H), 3.97-3.90 (m, 8H), 2.23 (s, 3H), 1.98 (s, 6H), 1.25 (t, J=8.0 Hz,3H). MS: m/z 394.9 (M+H⁺)

3-(2,6-Dimethyl-phenyl)-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.20-7.14 (m, 3H), 6.96 (s, 1H), 3.96 (brs,8H), 2.23 (s, 3H), 1.99 (s, 6H). MS: m/z 367.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-methylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=8.20 (brs, 1H), 7.20-7.14 (m, 3H), 6.56 (s,1H), 3.03 (s, 3H), 2.18 (s, 3H), 1.96 (s, 6H). MS: m/z 311.1 (M+H⁺).

7-Dimethylamino-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.26-7.11 (m, 3H), 6.64 (s, 1H), 3.33 (s,6H), 2.16 (s, 3H), 1.94 (s, 6H). MS: m/z 325.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-propyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.79 (dd, J=8.8, 6.4 Hz, 1H), 7.14-7.09 (m,2H), 6.71 (s, 1H), 3.99 (t, J=7.6 Hz, 2H), 3.90 (s, 3H), 3.34 (s, 3H),2.26 (s, 3H), 2.04 (s, 6H), 1.85-1.74 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).MS: m/z 367.2 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(methyl-propyl-amino)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.10 (dd, J=8.8, 6.0 Hz, 1H), 7.07-7.02 (m,2H), 6.52 (s, 1H), 3.92 (t, J=7.2 Hz, 2H), 3.29 (s, 3H), 2.16 (s, 3H),1.94 (s, 6H), 1.67-1.57 (m, 2H), 0.78 (t, J=7.2 Hz, 3H). MS: m/z 352.9(M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.20 (dd, J=8.4, 6.4 Hz, 1H), 7.15-7.12 (m,2H), 6.85 (s, 1H), 4.39 (q, J=7.2 Hz, 2H), 3.96-3.92 (m, 4H), 2.84-2.81(m, 4H), 2.47 (s, 3H), 2.29 (s, 3H), 2.02 (s, 6H), 1.37 (d, J=7.2 Hz,3H). MS: m/z 407.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CD₃OD): δ=7.22 (dd, J=8.8, 6.4 Hz, 1H), 7.17-7.15 (m,2H), 7.04 (s, 1H), 4.86-4.82 (m, 4H), 3.74-3.45 (m, 4H), 3.04 (s, 3H),2.26 (s, 3H), 1.99 (s, 6H). MS: m/z 379.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.18 (dd, J=8.8, 6.0 Hz, 1H), 7.14-7.09 (m,2H), 6.50 (s, 1H), 4.15-4.05 (m, 4H), 3.88 (s, 3H), 2.21 (s, 3H),2.11-2.05 (m, 4H), 2.04 (s, 6H). MS: m/z 365.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.64 (dd, J=8.8, 5.6 Hz, 1H), 7.16-7.12 (m,2H), 6.41 (s, 1H), 4.10-3.94 (m, 4H), 2.12 (s, 3H), 2.02-1.96 (m, 4H),1.95 (s, 6H). MS: m/z 351.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-piperidin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Methyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester.

¹HNMR (400 MHz, CDCl₃): δ=7.19 (dd, J=8.4, 6.4 Hz, 1H), 7.15-7.10 (m,2H), 6.86 (s, 1H), 4.15-4.05 (m, 4H), 3.89 (s, 3H), 3.88-3.81 (m, 4H),2.28 (s, 3H), 2.02 (s, 6H), 1.92-1.83 (m, 4H), 1.82-1.75 (m, 2H). MS:m/z 379.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-piperidin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-phenylamino-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.64 (dd, J=8.4, 6.0 Hz, 1H), 7.18-7.13 (m,2H), 6.78 (s, 1H), 3.83-3.75 (m, 4H), 2.18 (s, 3H), 1.94 (s, 6H),1.79-1.66 (m, 6H). MS: m/z 365.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Step 1

To a solution of7-chloro-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid ethyl ester (120 mg, 0.35 mmol) in DMF (6 mL) was addedpiperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.70 mmol) andK₂CO₃ (144 mg, 1.05 mmol). The resulting mixture was stirred in sealedtube at 100° C. overnight. Then DMF was removed in vacuum to give aresidue, which was purified by a silica gel column (PE/EA=5/1) to afford7-(4-tert-butoxycarbonyl-piperazin-1-yl)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (62.4 mg, yield: 38%) as a yellow solid.

Step 2

To a solution of7-(4-tert-butoxycarbonyl-piperazin-1-yl)-3-(2,6-dimethyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (58.6 mg, 0.126 mmol) in dioxane (20 mL) was added HCl/dioxane (5mL, 5 M in dioxane). The resulting mixture was stirred at roomtemperature for 3 hrs. Then the reaction mixture was concentrated invacuum to give a residue, which was purified by a reversed-phase column(B from 5-95, A: H₂O, B: ACN) to afford3-(2,6-dimethyl-phenyl)-2-methyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid (20.1 mg, yield: 44%) as a yellow solid.

¹HNMR (400 MHz, CD₃OD): δ=9.06 (brs, 2H), 7.23 (dd. J=8.8, 6.4 Hz, 1H),7.20-7.15 (m, 2H), 6.90 (s, 1H), 4.20-4.03 (m, 4H), 3.44-3.23 (m, 4H),2.00 (s, 3H), 1.94 (s, 6H). MS: m/z 365.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-7-methoxy-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d₆): δ=7.22-7.16 (m, 3H), 7.00 (s, 1H), 4.27 (s,3H), 2.19 (s, 3H), 1.94 (s, 6H). MS: m/z 311.9 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenoxy-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid Ethyl Ester

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, CDCl₃): δ=7.55 (t, J=8.0 Hz, 2H), 7.42 (t, J=7.2 Hz,1H), 7.30-7.34 (m, 2H), 7.24 (dd, J=8.4, 6.4 Hz, 1H), 7.20-7.14 (m, 2H),6.60 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 2.39 (s, 3H), 2.08 (s, 6H), 1.32(t, J=7.2 Hz, 3H). MS: m/z 402.1 (M+H⁺).

3-(2,6-Dimethyl-phenyl)-2-methyl-7-phenoxy-pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using general procedure of3-(2,6-dimethyl-phenyl)-2-methyl-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid.

¹HNMR (400 MHz, DMSO-d6): δ=7.64 (t, J=8.0 Hz, 2H), 7.60-7.53 (m, 2H),7.50 (t, J=7.2 Hz, 1H), 7.34-6.98 (m, 3H), 6.41 (s, 1H), 2.23 (s, 3H),1.95 (s, 6H). MS: m/z 373.8 (M+H⁺).

3-(4-fluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using the general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid. The starting material in Step 1 was 4-fluorophenylacetonitrile. InStep 3, 2,4-dioxo-hexanoic acid methyl ester was substituted for thecorresponding ethyl ester. In Step 4, the ester hydrolysis was performedusing potassium hydroxide in aqueous methanol in place of lithiumhydroxide in aqueous tetrahydrofuran.

¹H NMR (500 MHz, Methanol-d₄) δ 7.79 (ddd, J=8.4, 5.3, 2.5 Hz, 2H), 7.45(s, 1H), 7.28-7.07 (m, 2H), 3.89 (hept, J=6.9 Hz, 1H), 2.63 (s, 3H),1.49 (d, J=6.9 Hz, 6H). MS: m/z 314.22 (M+H⁺).

7-isopropyl-3-(4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (Example I) and5-isopropyl-3-(4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine-7-carboxylicAcid (Example II)

The title compounds were prepared using the general procedure of3-(4-fluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid. After Step 3, the two regioisomers were separated as methyl estersvia flash chromatography eluting with 10% to 33% ethyl acetate inhexane. After conversion of each regioisomer to the correspondingcarboxylic acid title compound, the structure assignment was finalizedafter NOE experiments (shown below).

Example I: 1H NMR (500 MHz, Methanol-d₄) δ 7.72-7.66 (m, 2H), 7.46 (s,1H), 7.09-7.04 (m, 2H), 3.92 (hept, J=6.9 Hz, 1H), 3.87 (s, 3H), 2.65(s, 3H), 1.51 (d, J=6.9 Hz, 6H). MS: m/z 326.22 (M+H⁺).

Example II: 1H NMR (500 MHz, Methanol-d₄) δ 7.71-7.59 (m, 1H), 7.14-6.93(m, 2H), 3.87 (s, 2H), 3.13 (hept, J=6.9 Hz, 1H), 2.59 (s, 2H), 1.36 (d,J=6.9 Hz, 3H). MS: m/z 324.06 (M−H⁻).

7-isopropyl-2-methyl-3-(p-tolyl)pyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using the general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid. The starting material in Step 1 was 4-methylphenylacetonitrile. InStep 3, methyl 5-methyl-2,4-dioxohexanoate was substituted for thecorresponding ethyl ester. In Step 4, the ester hydrolysis was performedusing lithium hydroxide in aqueous dioxane. ¹H NMR (500 MHz,Methanol-d₄) δ 7.25 (s, 2H), 7.03 (s, 2H), 3.98-3.85 (m, 1H), 2.47 (s,3H), 2.33 (s, 3H), 1.52 (d, J=6.7 Hz, 6H). MS: m/z 310.24 (M+H⁺).

7-cyclopropyl-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylicAcid

The title compound was prepared using the general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid. The starting material in Step 1 was phenylacetonitrile. In Step 3,methyl 4-cyclopropyl-2,4-dioxobutanoate was substituted for thecorresponding ethyl ester. In Step 4, the ester hydrolysis was performedusing lithium hydroxide in aqueous dioxane. ¹H NMR (500 MHz,Methanol-d₄) δ 7.15 (s, 2H), 7.12-7.04 (m, 3H), 7.02 (d, J=7.2 Hz, 1H),2.89 (dt, J=8.4, 3.9 Hz, 1H), 2.37 (s, 3H), 1.50-1.31 (m, 2H), 1.29-1.10(m, 2H). MS: m/z 294.20 (M+H⁺).

7-isopropyl-3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylic Acid

The title compound was prepared using the general procedure of3-(2-fluoro-phenyl)-7-isopropyl-2-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxylicacid. Commencing at Step 3 using 4-phenyl-1H-pyrazol-3-amine and methyl5-methyl-2,4-dioxohexanoate was substituted for the corresponding ethylester. In Step 4, the ester hydrolysis was performed using lithiumhydroxide in aqueous dioxane. ¹H NMR (500 MHz, Chloroform-d) δ 8.59 (s,1H), 7.98-7.93 (m, 2H), 7.62 (s, 1H), 7.53 (t, J=7.8 Hz, 2H), 7.42-7.36(m, 1H), 4.01 (hept, J=6.9 Hz, 1H), 1.54 (d, J=6.9 Hz, 6H). MS: m/z282.21 (M+H⁺).

3-(2,6-dimethylphenyl)-N-hydroxy-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxamide

To a mixture of3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (50 mg, 0.16 mmol) and triethylamine (0.09 mL, 0.65 mmol) in DCM (2mL) was added HATU (60 mg, 0.16 mmol). The mixture was stirred for 15minutes prior to the addition of hydroxylamine hydrochloride (30 mg,0.43 mmol) after which the mixture was maintained at ambient temperatureovernight. The crude reaction mixture was partitioned with DCM and waterand the organic phase was concentrated. The residue was purified byprep-HPLC (ACN/H₂O) to afford3-(2,6-dimethylphenyl)-N-hydroxy-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxamide(16.8 mg, 32%) as a yellow solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.46(s, 1H), 7.27-7.23 (m, 1H), 7.19 (d, J=7.5 Hz, 2H), 3.98 (hept, J=6.9Hz, 1H), 2.35 (s, 3H), 2.03 (s, 6H), 1.52 (d, J=6.9 Hz, 6H) rotomersobserved. MS: m/z 339.34 (M+H⁺).

4-isopropyl-7,8,9,10-tetrahydropyrimido[1,2-b]indazole-2-carboxylic AcidStep 1

A solution of 2-oxocyclohexanecarbonitrile (500 mg, 4.06 mmol) andhydrazine hydrate (410 mg, 8.2 mmol) in EtOH (10 mL) was stirred atreflux overnight. The solvent was removed in vacuo and the resultingyellow residue 4,5,6,7-tetrahydro-2H-indazol-3-amine (520 mg, 93%) wasused without purification. ¹H NMR (500 MHz, Chloroform-d) δ 4.21 (s,3H), 2.54 (t, J=5.5 Hz, 2H), 2.32 (t, J=5.4 Hz, 2H), 1.83-1.67 (m, 4H).

Step 2

A solution of methyl 5-methyl-2,4-dioxohexanoate (180 mg, 1.05 mmol) and4,5,6,7-tetrahydro-2H-indazol-3-amine (140 mg, 1.02 mmol) in MeOH (5 mL)was prepared at ambient temperature then warmed to reflux and maintainedovernight. The solvent was evaporated and the crude residue was purifiedon silica gel eluting with DCM to afford methyl4-isopropyl-7,8,9,10-tetrahydropyrimido[1,2-b]indazole-2-carboxylate(121 mg, 44%) as a yellow residue. ¹H NMR (500 MHz, Chloroform-d) δ 7.37(s, 1H), 4.05 (s, 3H), 3.91 (hept, J=6.9 Hz, 1H), 2.96 (td, J=6.1, 3.3Hz, 4H), 1.98 (tdd, J=6.5, 5.1, 2.3 Hz, 2H), 1.91 (ddp, J=8.9, 5.9, 2.6Hz, 2H), 1.47 (d, J=6.9 Hz, 6H).

Step 3

To a solution of methyl4-isopropyl-7,8,9,10-tetrahydropyrimido[1,2-b]indazole-2-carboxylate(121 mg, 0.44 mmol) in THF (5 mL) was added 0.5 M LiOH (1.3 mL, 0.68mmol) and the mixture was stirred at ambient temperature overnight. Thereaction mixture was acidified with aqueous NaHSO₄ and the product wasextracted with EtOAc. After evaporation, the residue was purified onsilica gel eluting with 30-50% EtOAc in hexanes to afford4-isopropyl-7,8,9,10-tetrahydropyrimido[1,2-b]indazole-2-carboxylic acid(108 mg, 94%) as a yellow solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.45(s, 1H), 3.93 (hept, 6.8 Hz, 1H), 2.98 (t, J=6.2 Hz, 2H), 2.88 (t, J=6.1Hz, 2H), 1.99 (ddt, J=8.4, 6.5, 2.7 Hz, 2H), 1.96-1.89 (m, 2H), 1.47 (d,J=6.9 Hz, 6H). MS: m/z 260.23 (M+H⁺).

1-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2,2,2-trifluoroethanoneStep 1

A solution of methyl3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(62 mg, 0.18 mmol) in THF (1 mL) was treated with 1.5 M/toluene DIBAL-Hsolution (0.26 mL, 0.39 mmol) and was stirred at ambient temperature 1hour. The reaction was partitioned with EtOAc and aqueous KOH. Solidswere filtered over Celite and were washed with EtOAc. The combinedorganics were dried and condensed to afford(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)methanol(52 mg, 91%) as a residue which was used without further purification.¹H NMR (500 MHz, Chloroform-d) δ 7.15 (dd, J=8.4, 6.6 Hz, 1H), 7.09 (d,J=7.5 Hz, 2H), 6.43 (s, 1H), 4.64 (bs, 2H), 3.86 (hept, J=6.8 Hz, 1H),2.22 (s, 3H), 1.97 (s, 6H), 1.40 (d, J=6.9 Hz, 6H). MS: m/z 310.34(M+H⁺).

Step 2

A solution of(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)methanol(50 mg, 0.16 mmol) in DCE (2 mL) was treated with manganese(IV)oxide(100 mg, 1.15 mmol) and stirred at reflux overnight. The solids wereremoved by filtration over Celite then the solvent was condensed toafford3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carbaldehyde(30 mg, 60%) as a yellow residue. ¹H NMR (500 MHz, Chloroform-d) δ 9.83(s, 1H), 7.17 (m, 1H), 7.12 (d, J=7.6 Hz, 2H), 3.89 (hept, J=6.8 Hz,1H), 2.29 (s, 3H), 1.98 (s, 6H), 1.44 (d, J=6.9 Hz, 6H). MS: m/z 308.30(M+H⁺).

Step 3

A solution of3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carbaldehyde(15 mg, 49 μmol) in DCM (1 mL) was treated with trimethylsilyltrifluoromethane (50 mg, 0.35 mmol) followed by dropwise addition of 1M/THF TBAF solution. After 1 hour the reaction was partitioned withEtOAc and water. The organics were then dried and evaporated to providea residue which was purified on silica gel eluting with 20% EtOAc inhexanes to afford1-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2,2,2-trifluoroethanol(11 mg, 60%) as a residue. ¹H NMR (500 MHz, Chloroform-d) δ 7.27-7.25(m, 1H), 7.19 (d, J=7.6 Hz, 2H), 6.71 (s, 1H), 5.06-4.98 (m, 2H), 3.99(hept, J=6.9 Hz, 1H), 2.35 (s, 3H), 2.05 (d, J=9.4 Hz, 6H), 1.52 (dd,J=8.0, 6.9 Hz, 6H). MS: m/z 378.37 (M+H⁺).

Step 4

A mixture of1-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2,2,2-trifluoroethanol(8 mg, 21 mmol) and manganese(IV)oxide (50 mg, 0.57 mmol) in DCE (1 mL)was stirred at reflux overnight. The solids were removed by filtrationover Celite then the solvent was condensed to afford1-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2,2,2trifluoroethanone (4 mg, 50%) as a residue. ¹H NMR (500 MHz,Chloroform-d) δ 7.25 (dd, J=8.3, 6.8 Hz, 1H), 7.17 (d, J=7.5 Hz, 2H),5.82 (s, 1H), 3.69 (h, J=7.0 Hz, 1H), 2.16 (s, 3H), 2.10 (s, 6H), 1.43(d, J=6.9 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 174.87, 160.56, 158.64,151.56, 138.82, 136.69, 128.53, 127.87, j127.68, 100.55, 99.32, 28.34,20.62, 20.31, 12.80. MS: m/z 296.28 (M−COCF₃+H₂O⁺ ionization artifact).

N-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetamideStep 1

To a mixture of3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (100 mg, 0.32 mmol) and triethylamine (50 μL, 0.36 mmol) in DCM (10mL) was added DPPA (90 mg, 0.33 mmol) while being maintained in an icewater bath for an additional 2 hours. The reaction was let warm toambient temperature overnight. The mixture was filtered through a 2 g.plug of silica gel and the solvent was evaporated to provide a residuethat was used directly without purification. The sample was refluxed inwet dioxane for 1 hour then condensed to a yellow oil3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-amine(83 mg, 91%). ¹H NMR (500 MHz, Chloroform-d) δ 7.14 (d, J=7.5 Hz, 2H),7.06 (dd, J=7.9, 5.9 Hz, 1H), 5.87 (bs, 1H) 5.82 (s, 1H), 4.90 (bs, 1H)3.77 (hept, J=6.9 Hz, 1H), 2.18 (s, 3H), 2.06 (s, 6H), 1.41 (d, J=6.9Hz, 6H). MS: m/z 295.36 (M+H⁺).

Step 2

A solution of crude3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-amine(25 mg, 85 μmol max) and triethylamine (70 μL, 500 μmol) in DCM (1 mL)was treated with a catalytic amount of DMAP followed by acetic anhydride(32 mL, 340 mmol). The mixture was stirred overnight then waspartitioned with DCM and water. The organics were evaporated and thecrude material was purified on silica gel eluting with DCM to affordN-(3-(2,6-dimethylphenyl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetamideas a residue (7 mg, 25%). ¹H NMR (500 MHz, Chloroform-d) δ 8.06 (s, 1H),7.75 (s, 1H), 7.22 (dd, J=8.5, 6.4 Hz, 1H), 7.17 (d, J=7.5 Hz, 2H), 3.93(hept, J=6.9 Hz, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.06 (s, 6H), 1.51 (d,J=6.9 Hz, 6H). MS: m/z 337.36 (M+H⁺).

Biological Data

This example illustrates the biological activity of various compoundstested against the APJ receptor.

Commercially available cell lines were used to screen chemical librariesto identify compounds that potently and selectively activated the humanapelin receptor. The assays disclosed herein were performed using celllines from DiscoveX, Inc.

Biological activity was determined to the cell-based assay. This assaydetects activation of the receptor by reporting on intracellular cyclicadenosine monophosphate (cAMP) level. Chinese hamster ovary cellsengineered to express the stably integrated human appellant receptor(APJ, AGTRL-one, APLNR), pleaded into the wells of the microtiter plate.Cells were stimulated with source: to increase intracellular cyclic AMP.Immediately following, compounds were added to the range of finalconcentrations 0.0-100 μM, in DMSO (not to exceed a final DMSOconcentration greater than 1% v/v), and allowed to incubate with thecells for 0.5 h. At the end of the incubation, cells were lysed to stopAPJ signaling and cAMP was quantified using a commercially availablecompetitive immunoassay kit that applies homogenous time-resolvedflorescence energy transfer (TR-FRET). The assay is based on thecompetition between a europium (Eu) chelate-labeled cAMP donor tracerand cellular cAMP for binding sites on a cAMP-specific monoclonalantibody labeled with an acceptor fluorophore. When antibodies are boundto the cAMP tracer light emissions at 320 nm stimulate the energytransfer from the donor to the acceptor, which in turn emits light at665 nm. In the presence of competitive unlabeled cAMP (derived from theactivity of the receptor or forskolin-stimulated production of cAMP),the labelled cAMP tracer is dissociated from the cAMP antibody,resulting in a loss of FRET signal. The amount of light emitted by theFRET is inversely proportional to the cAMP generated by thecell/receptor system. Potency and efficacy at APJ are reported inreference to the canonical APJ receptor agonist apelin-13 when tested at1 nM.

Compound competency is reported as the effective concentration requiredto effect 50% (EC 50) of the control (apelin—13, 1 nM) response inmicromole are (μM) units. Compound efficacy (% response) is reported asa percentage of the maximal apein-13 response at 1 nM (control).Potencies were calculated by fitting a four-point logistic curve toconcentration response consisting of at least 10 discrete data pointsspanning effective range of the compounds in the cell-based assay thatmeasures cAMP. In Table 1, the Potency Categories are A, B, C and D.Category A EC50>500 nM; Category B 200<EC50<500 nM; Category C100<EC50<200 nM; Category D<100 nM.

Although the present invention has been described in terms of specificexemplary embodiments and examples, it will be appreciated that theembodiments disclosed herein are for illustrative purposes only andvarious modifications and alterations might be made by those skilled inthe art without departing from the spirit and scope of the invention asset forth in the following claims.

1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areeach independently selected from the group consisting of H, halogen,cyano, alkyl, aryl, alkoxy, phenoxy, amino, aniline, —CO₂H, —CO₂R⁶, and—CON(R⁷)₂; R³ is selected from the group consisting of hydrogen, —CN,alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, haloalkoxy,phenyl, and 5- or 6-membered heteroaryl; R⁴ is selected from the groupconsisting of hydrogen, —CN, alkyl, cycloalkyl, heterocycloalkyl,alkoxy, haloalkyl, haloalkoxy, phenyl, and 5- or 6-membered heteroaryl;R⁵ is selected from the group consisting of —CO₂H, —CO₂R⁸, —CON(R⁹)₂,alkyl, aryl, and alkoxy; and R⁶-R⁹ are each independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl,alkoxy, haloalkyl, haloalkoxy, phenyl, amino, and 5- or 6-memberedheteroaryl.
 2. (canceled)
 3. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of claim 1, or apharmaceutically acceptable salt thereof.
 4. A method for inhibitingapelin receptor activity in a subject, comprising administering to thesubject in need thereof a pharmaceutical composition of claim
 3. 5. Themethod of claim 4, wherein the subject has a disease or disorderselected from the group consisting of a cardiovascular disease ordisorder, coronary heart disease, stroke, heart failure, cardiomyopathy,myocardial infarction, left ventricular dysfunction, cardiachypertrophy, myocardial remodeling, and valvular heart disease.
 6. Themethod of claim 4, wherein the subject has a disease or disorderselected from the group consisting of a metabolic disease, a metabolicdisorder, insulin resistance, diabetes mellitus, a diabetic latecomplication, a diabetic macrovasculopathy, a diabeticmicrovasculopathy, diabetic nephropathy, diabetic retinopathy, diabeticneuropathy, and cardiac autonomic neuropathy.
 7. The method of claim 4,wherein the subject has a disease or disorder selected from the groupconsisting of acute renal failure, a central nervous system-dependentdisturbed fluid homeostasis, a central nervous system-independentdisturbed fluid homeostasis, chronic renal failure, and hypertension. 8.The method of claim 4, wherein the subject has a disease or disorderselected from the group consisting of atherosclerosis, ischemia damage,nonfunctional blood vessels, peripheral arterial occlusive disease, avascular disease and a vascular disorder.
 9. The method of claim 4,wherein the subject has an infectious disease.
 10. The method of claim5, wherein the heart failure is selected from the group consisting ofdiabetic heart failure, diastolic heart failure, heart failure withpreserved ejection fraction, and systolic heart failure.
 11. The methodof claim 5, wherein the left ventricular dysfunction is left ventriculardysfunction after myocardial infarction; and wherein the myocardialremodeling is myocardial remodeling after cardiac surgery or myocardialremodeling after infarction.
 12. The method of claim 6, wherein themetabolic diseases or metabolic disorder is metabolic syndrome.
 13. Themethod of claim 7, wherein the hypertension is selected from the groupconsisting of portal hypertension, pulmonary hypertension, and systolichypertension.
 14. The method of claim 8, wherein the ischemia damage isselected from the group consisting of ischemia damage of the heart,ischemia damage of the kidney, ischemia damage of the retina, or acombination thereof; wherein the reperfusion damage is selected from thegroup consisting of reperfusion damage of the heart, reperfusion damageof the kidney, reperfusion damage of the retina, or a combinationthereof; and wherein the vascular disease or vascular disorder isselected from the group consisting of vascular hypertrophy, a vascularpermeability disorder, vascular remodeling, and vascular stiffness. 15.The method of claim 14, wherein the vascular permeability disorder isvascular permeability.
 16. The compound of claim 1, wherein: R¹ is H oralkyl; and R² is H or alkyl.
 17. The compound of claim 1, wherein R³ isalkyl.
 18. The compound of claim 1, wherein R⁴ is alkyl.
 19. Thecompound of claim 1, wherein R⁵ is C(O)OH.
 20. The compound of claim 1,wherein: R⁵ is C(O)OR⁸; and R⁸ is alkyl.
 21. The compound of claim 1,wherein: R⁵ is C(O)N(R⁹)₂; and each R⁹ is independently H or alkyl.